- Email: [email protected]
Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease
Advances in Biological Regulation xxx (2016) 1e6
Contents lists available at ScienceDirect
Advances in Biological Regulation journal homepage: www.elsevier.com/locate/jbior
Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease Taisuke Tomita* Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 December 2016 Received in revised form 24 December 2016 Accepted 4 January 2017 Available online xxx
Amyloid-b peptide (Ab) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Ab is derived from amyloid-b precursor protein that is sequentially cleaved by two aspartate proteases, b- and g-secretases. Secreted Ab is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Ab by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, the dynamics of cerebral Ab, called as “Ab economy”, would be the mechanistic basis of AD pathogenesis. Partial loss of g-secretase activity leads to the increased generation of toxic Ab isoforms, indicating that activation of g-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a b-secretase enzyme, has emerged as a prime drug target for lowering brain Ab levels. Recent studies revealed the decreased clearance of Ab in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Ab economy, and development of effective treatment and diagnostics for AD. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Alzheimer disease Amyloid-b peptide Membrane protein Protease Secretase Degradation
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proteolytic processing of APP by b- and g-secretases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of b- and g-secretase activities as a potential therapeutic strategy . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic approaches based on Ab degradation pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Permission note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
00 00 00 00 00 00 00 00 00
* Corresponding author. Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jbior.2017.01.001 2212-4926/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
2
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
1. Introduction Alzheimer disease (AD) is characterized by extensive neuronal loss and the appearance of two types of neuropathological hallmarks; senile plaques and neurofibrillary tangles (Goedert, 2015; Selkoe and Hardy, 2016; Sperling et al., 2014). Senile plaques present extracellularly and consist mainly of amyloid-b protein (Ab). Ab is produced from its precursor called amyloid precursor protein (APP) through sequential cleavage by b- and g-secretases (De Strooper et al., 2010) (Fig. 1). Neurofibrillary tangles are comprised of intraneuronal aggregation of microtubule-binding protein, tau. Importantly, genetic mutations in APP gene found in patients of the dominantly inherited form of familial AD cause increased production and/or aggregation of Ab (Selkoe and Hardy, 2016). Moreover, genes encoding multipass membrane proteins called presenilin (PS) 1 and 2 were identified in familial AD patients (Sherrington et al., 1995). These mutations alter the g-secretase-mediated cleavage of APP, leading to increased production of the more aggregation-prone form of Ab (Borchelt et al., 1996; Tomita et al., 1997). APP locus duplication was also identified in autosomal dominant early-onset AD cases (Rovelet-Lecrux et al., 2006). And recently, a rare coding mutation A673T in the APP gene that reduces the b-secretase-mediated cleavage has been identified in the elderly without AD as a protective allele (Jonsson et al., 2012), supporting the central role of Ab in the development of AD. In contrast, aberrant tau aggregates are present not only in AD, but several neurodegenerative disease such as progressive supranuclear palsy, Pick's disease, corticobasal degeneration or frontotemporal dementia, the latter being characterized by massive neuronal loss and the formation of tangles without deposition of Ab (Iqbal et al., 2016). Tau is a phosphoprotein that promotes the assembly and stabilization of microtubules. Tau also interacts with several proteins such as phospholipase C to regulate intracellular signaling involved in the neuronal functions (Gunawardana et al., 2015; Yang et al., 2016). Aggregated tau undergoes hyperphosphorylation, which promotes dissociation of tau from the microtubules and self-aggregation. Importantly, mutations in tau gene are linked to autosomal dominant form of frontotemporal dementia, indicating that tau pathology correlates with neuronal death. In fact, biomarker observational studies suggest a pathological model of AD that brain Ab deposits early, before neurodegeneration biomarker changes (i.e., brain atrophy and increased cerebrospinal fluid (CSF) tau) and clinical symptoms occur (Jack et al., 2010). Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant familial AD patients also support this model (Bateman et al., 2012; Reiman et al., 2012). Finally, tangle pathology was induced/exacerbated by aggregated Ab in model animals (Gotz et al., 2001; Lewis et al., 2001), and tau was required for the Ab mediated neurotoxicity (Roberson et al., 2007). Thus, these observations clearly suggest that Ab is an initiator molecule of AD pathogenesis, and tau is associated with neuronal dysfunction and cell death (Sperling et al., 2014). 2. Proteolytic processing of APP by b- and g-secretases APP is processed by the non-amyloidogenic or amyloidogenic pathway (De Strooper et al., 2010). In the non-amyloidogenic pathway, APP is first cleaved at its juxtamembrane region by a-secretase, leading to generation of the soluble N-terminal fragment sAPPa and C-terminal stub called C83. A disintegrin and metalloprotease 10 (ADAM10) is the main enzyme responsible for a-secretase activity (Kuhn et al., 2010). In the amyloidogenic pathway, b-site APP-cleaving enzyme 1 (BACE1) endoproteolyzes APP at ectodomain, yielding the secreted sAPPb and a longer C-terminal fragment, C99 (Yan, 2016; Yan and Vassar, 2014). Then both C83 and C99 are subjected to intramembrane cleavage by g-secretase to release extracellularly p3 or Ab, respectively. As BACE1 is a single-span membrane-anchored aspartic protease expressed in neuronal cells, Ab is mainly generated from neurons. g-Secretase-mediated cleavage occurs several cell types, and generates heterogeneity in the Cterminal length of Ab, mainly producing Ab40 and Ab42. Ab42 is the most toxic and aggregation-prone Ab species and is the predominant species deposited in AD brains (Iwatsubo et al., 1994). Notably, it took about 10 years to gain a comprehensive understanding of g-cleavage at molecular level, because the g-secretase mediated hydrolysis of APP should be occurred within the transmembrane domain (TMD) that is embedded in the hydrophobic environment. Several biochemical, cell
Fig. 1. Schematic diagram of proteolytic processing of APP and Ab. b-Secretase/BACE1 cleaves APP to generate sAPPb and C99, the latter being further processed by g-secretase. These sequential cleavages result in the production of Ab, which is a main component of the senile plaque. The minimal g-secretase complex is comprised of PS, nicastrin, Aph-1 and Pen-2. Ab is then metabolized by proteolytic processing by Ab-degrading enzymes and other catabolic processes (i.e., phagocytosis, passive and active transport, diffusion).
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
3
biological and genetic studies now revealed that g-secretase is a membrane complex comprised of PS, nicastrin, Aph-1 and Pen-2, and PS is the catalytic molecule responsible for g-secretase-mediated intramembrane cleavage (Takasugi et al., 2003; Tomita, 2014). And recently, the atomic structure of human g-secretase complex was resolved by single-particle cryo-electron microscopy (Bai et al., 2015). Catalytic aspartates are faced to hydrophilic cavity in the PS formed within the lipid bilayer, supporting a notion that PS itself executes intramembrane proteolysis. 3. Regulation of b- and g-secretase activities as a potential therapeutic strategy With regard to the development of AD therapeutics, lowering Ab production by inhibition of b- or g-secretase activity has been a prime strategy. In fact, several cell-permeable g-secretase inhibitors have been identified by cell-based screening and combinatorial chemistry. However, these g-secretase inhibitors block the cleavage of not only APP but other g-secretase substrates, including notch receptor that plays an important role in developmental process and maintenance of stem cells. Indeed, a phase 3 trial of semagacestat from Eli Lilly was discontinued because of increased incidences of skin cancer and worsening of cognitive function (Doody et al., 2013). Clinical trial of different g-secretase inhibitor, avagacestat from BristolMyers-Squibb, was also halted because of similar adverse effects (Amanatkar et al., 2016), suggesting that the development of g-secretase inhibitors as AD therapeutics is difficult. Other compounds called g-secretase modulators (GSMs) have been highlighted to alter Ab production without affecting notch signaling (Crump et al., 2013). GSMs only shift the production away from the aggregation-prone longer Ab species, increasing the production of the shorter Ab species. Phase 3 trial of a first generation Ab42-lowering GSM, R-Flurbiprofen (tarenflurbil), was terminated because it failed to achieve a significant therapeutic effect. Currently, second generation GSMs with a phenylimidazole backbone have been tested in clinical trials. Intriguingly, the g-secretase activity is also modulated by endogenous lipids and their analogues (e.g., steroids, sphingolipids, ceramide) (Jung et al., 2013; Osenkowski et al., 2008; Takasugi et al., 2013, 2015). Thus, enzymes involved in the metabolism of these lipids would be novel targets for the modulation of the g-secretase activity, Ab production and brain Ab economy (Fonseca et al., 2010; Shamseddine et al., 2015). Regarding the molecular mechanisms of the synthetic GSMs, we have recently revealed that these compounds directly target to PS to allosterically activate the g-secretase activity using chemical biology approaches (Ohki et al., 2011; Takeo et al., 2014). Moreover, artificial genetic mutations in PS1 that activates g-secretase activity reduce Ab42 production in mammalian cells (Futai et al., 2016). Supporting this notion, familial AD-linked mutations in PS1 that overproduce Ab42 causes a partial loss-of-function in the enzymatic activity of g-secretase (Chavez-Gutierrez et al., 2012). Thus, development of small compounds that activate, but not inhibit, the g-secretase activity using the detailed structural information of g-secretase would pave the way for the development of novel efficient AD therapy. BACE1 knockout mice crossed with APP transgenic mice do not produce Ab, nor show Ab deposition in the brain, suggesting the critical role of BACE1 in Ab amyloidosis (Cai et al., 2001; Luo et al., 2001). Genetic finding of protective allele in non-demented individuals that reduce b-cleavage also support the notion that inhibition of BACE1 activity is a promising strategy against AD (Yan and Vassar, 2014). However, because of the largely open catalytic site structure, drug development of BACE1 inhibitor has proven challenging (Ghosh and Osswald, 2014). After intense efforts in both academia and industry, several BACE1 inhibitors have recently entered human clinical trials. Verubecestat (MK-8931) from Merck Research Laboratories is a potent and selective BACE1 inhibitor that reduced brain concentrations of Ab in rats, monkeys and human subjects (Kennedy et al., 2016). Recently, AstraZeneca and Eli Lilly announced joint development of AZD-3293, which is a potent BACE1 inhibitor and successfully decreased the CSF Ab in human healthy volunteers, in 5-year phase II/III trial. In addition to them, JNJ-54861911 from Janssen/Shionogi, E2609 from Eisai/Biogen, and CNP520 from Novartis/Amgen have been under development as AD therapeutics (Yan, 2016). 4. Therapeutic approaches based on Ab degradation pathway In brain, soluble form of Ab is rapidly eliminated with a half-life of ~30 min (Shibata et al., 2000; Yamada et al., 2009), suggesting that Ab is actively degraded. Thus, the homeostatic balance of production and degradation of Ab, denoted as Ab economy, is a critical determinant for brain Ab levels (Karran et al., 2011) (Fig. 2). Moreover, Mawuenyega and colleagues observed decreased clearance rather than increased production of Ab in the CSF of sporadic AD patients (Mawuenyega et al., 2010). Thus, in addition to overproduction of Ab, decreased Ab degradation would lead to aberrant brain Ab economy and underlie the pathogenic mechanism of AD. However, whole picture of Ab catabolism in brain still remains unclear. In vitro studies revealed that Ab is degraded by several proteases with diverse characteristics (Saido and Leissring, 2012; Saido, 2013). Among them, neprilysin (Iwata et al., 2000) and insulin-degrading enzyme (IDE) (Qiu et al., 1997) are well-established Abdegrading enzymes that has been extensively investigated for its role in the regulation of brain Ab level in vitro and in vivo. Brains of KO mice of these proteases showed 1.4e2 fold increase in brain Ab levels (Farris et al., 2003; Iwata et al., 2001; Miller et al., 2003). Moreover, transgenic overexpression of either neprilysin or IDE reduces the amyloid pathology in vivo, suggesting that each protease is a rate limiting enzyme in the determination of cerebral Ab concentrations. In fact, enzymatic character and molecular nature of these peptidases are distinct. Neprilysin is a single span membrane associated metalloprotease expressed in neurons, not in glia, and axonally transported to presynaptic terminals (Fukami et al., 2002). Notably, somatostatin upregulated neprilysin activity in primary cortical neurons, suggesting that somatostatin pathway is a pharmacological-target for AD therapeutics based on the upregulation of neprilysin activity (Saito et al., 2005). IDE is also zinc-metalloprotease, but present in both cytosol and extracellular space, whereas IDE lacks a conventional signal sequence. Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
4
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
Fig. 2. Altered brain Ab economy in the AD pathogenesis. Brain Ab economy is regulated by the rates of Ab production and degradation/clearance. Note that almost all genetic mutations/variations found in autosomal dominant familial AD cases (FAD) affect the production or aggregation of Ab. In contrast, decreased Ab clearance rate is implicated in the sporadic AD cases (SAD). Both alterations cause the increase in the soluble Ab level and aggregability, thereby leading the deposition of Ab as senile plaques.
IDE is expressed variety of cell lines including microglia. However, as insulin is a better endogenous substrate than Ab for IDE, altered insulin signaling would be presumed by upregulation of IDE expression and/or activity. Of note, neither neprilysin nor IDE can degrade the fibrillar Ab, indicating that aggregation status of Ab peptides also impacts on the Ab economy regulated by these peptidases. Recently, we have identified kallikrein-related peptidase 7 (KLK7) as a novel Ab-degrading enzyme secreted the astrocytes (Kidana, Tatebe, Tomita et al., unpublished data). Notably, KLK7 is able to cleave fibrillar form of Ab and attenuate its cell toxicity in primary neuronal culture (Shropshire et al., 2014), suggesting the importance of KLK7 in the development of amyloid pathology. Moreover, expression level of KLK7 was significantly reduced in the sporadic AD patients (Diamandis et al., 2004). Thus, upregulation of KLK7 would provide beneficial effect for individuals who has already developed the senile plaques. 5. Conclusions Advances in genetics and clinically relevant sequencing applications have provided important information of aberrant Ab production machinery (i.e., altered b- and g-secretase-mediated cleavages) in the pathomechanism of familial AD. Based on these observations, large phase II/III trials of b-secretase inhibitor are currently ongoing. In addition, antibody-mediated clearance of Ab has been tested in clinical trials, although the efficacies of antibody drugs on the amyloid pathology and neurological symptoms were varied (Doody et al., 2014; Hock et al., 2002; Salloway et al., 2014; Sevigny et al., 2016). Thus, pharmacological stimulation of Ab-degrading activity would provide the different approach to modify brain Ab economy. However, it still remains unknown why Ab is deposited in the sporadic AD cases, in which decreased Ab clearance was implicated. One possibility is that aging affects the catabolic mechanism of Ab in the brain. In fact, age-dependent Ab accumulation in the brains of nondemented elderly precedes the formation of senile plaques (Funato et al., 1998). It would be intriguing whether the proteolytic activity of physiological Ab degrading enzyme(s) declines in cognitively normal elderly. To do this, identification of reliable surrogate biomarker that reflects the Ab-degrading activity in the brain is needed. In addition to Ab, development of tau-targeted therapeutics (e.g., vaccination (Novak et al., 2016), anti-tau antibody (Lee et al., 2016), inhibition of O-GlcNAcylation (Yang and Suh, 2014; Yuzwa et al., 2012)) has been highlighted (Iqbal et al., 2016; Mullard, 2016). Notably, several proteases have been implicated in the tau toxicity (Chesser et al., 2013; Zhao et al., 2016). Nevertheless, further researches on these proteolytic mechanisms may provide new promising therapeutic/prevention strategies for AD. Conflict of interest The author declares no competing financial interests. Permission note All material in the manuscript is original contents. Acknowledgements This work was supported in part by a Grant-in-Aid for Scientific Research (A) [15H02492] from the Japan Society for the Promotion of Science, Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development [16dm0107056h0001] and grant from the Pharmacological Research Foundation, Tokyo. Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
5
References Amanatkar, H.R., Papagiannopoulos, B., Grossberg, G.T., 2016. Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies. Expert Rev. Neurother. 1e10. Bai, X.C., Yan, C., Yang, G., Lu, P., Ma, D., Sun, L., Zhou, R., Scheres, S.H., Shi, Y., 2015. An atomic structure of human gamma-secretase. Nature 525 (7568), 212e217. Bateman, R.J., Xiong, C., Benzinger, T.L., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Cairns, N.J., Xie, X., Blazey, T.M., Holtzman, D.M., Santacruz, A., Buckles, V., Oliver, A., Moulder, K., Aisen, P.S., Ghetti, B., Klunk, W.E., McDade, E., Martins, R.N., Masters, C.L., Mayeux, R., Ringman, J.M., Rossor, M.N., Schofield, P.R., Sperling, R.A., Salloway, S., Morris, J.C., Dominantly Inherited Alzheimer, N., 2012. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367 (9), 795e804. Borchelt, D.R., Thinakaran, G., Eckman, C.B., Lee, M.K., Davenport, F., Ratovitsky, T., Prada, C.M., Kim, G., Seekins, S., Yager, D., Slunt, H.H., Wang, R., Seeger, M., Levey, A.I., Gandy, S.E., Copeland, N.G., Jenkins, N.A., Price, D.L., Younkin, S.G., Sisodia, S.S., 1996. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17 (5), 1005e1013. Cai, H., Wang, Y., McCarthy, D., Wen, H., Borchelt, D.R., Price, D.L., Wong, P.C., 2001. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat. Neurosci. 4 (3), 233e234. Chavez-Gutierrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., Wiltfang, J., Serneels, L., Karran, E., Gijsen, H., Schymkowitz, J., Rousseau, F., Broersen, K., De Strooper, B., 2012. The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J. 31 (10), 2261e2274. Chesser, A.S., Pritchard, S.M., Johnson, G.V., 2013. Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease. Front. Neurol. 4, 122. Crump, C.J., Johnson, D.S., Li, Y.M., 2013. Development and mechanism of gamma-secretase modulators for Alzheimer's disease. Biochemistry 52 (19), 3197e3216. De Strooper, B., Vassar, R., Golde, T., 2010. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. reviews. Neurol. 6 (2), 99e107. Diamandis, E.P., Scorilas, A., Kishi, T., Blennow, K., Luo, L.Y., Soosaipillai, A., Rademaker, A.W., Sjogren, M., 2004. Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia. Clin. Biochem. 37 (3), 230e237. Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R.G., Aisen, P.S., , Alzheimer's Disease Cooperative Study Steering, C, Siemers, E., Sethuraman, G., Mohs, R., Semagacestat Study, G., 2013. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369 (4), 341e350. Doody, R.S., Thomas, R.G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P.S., Siemers, E., Liu-Seifert, H., Mohs, R., , Alzheimer's Disease Cooperative Study Steering, C, Solanezumab Study, G., 2014. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370 (4), 311e321. Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E.A., Frosch, M.P., Eckman, C.B., Tanzi, R.E., Selkoe, D.J., Guenette, S., 2003. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc. Natl. Acad. Sci. U. S. A. 100 (7), 4162e4167. Fonseca, A.C., Resende, R., Oliveira, C.R., Pereira, C.M., 2010. Cholesterol and statins in Alzheimer's disease: current controversies. Exp. Neurol. 223 (2), 282e293. Fukami, S., Watanabe, K., Iwata, N., Haraoka, J., Lu, B., Gerard, N.P., Gerard, C., Fraser, P., Westaway, D., St George-Hyslop, P., Saido, T.C., 2002. Abeta-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology. Neurosci. Res. 43 (1), 39e56. Funato, H., Yoshimura, M., Kusui, K., Tamaoka, A., Ishikawa, K., Ohkoshi, N., Namekata, K., Okeda, R., Ihara, Y., 1998. Quantitation of amyloid beta-protein (A beta) in the cortex during aging and in Alzheimer's disease. Am. J. Pathol. 152 (6), 1633e1640. Futai, E., Osawa, S., Cai, T., Fujisawa, T., Ishiura, S., Tomita, T., 2016. Suppressor mutations for presenilin 1 familial alzheimer disease mutants modulate gamma-secretase activities. J. Biol. Chem. 291 (1), 435e446. Ghosh, A.K., Osswald, H.L., 2014. BACE1 (beta-secretase) inhibitors for the treatment of Alzheimer's disease. Chem. Soc. Rev. 43 (19), 6765e6813. Goedert, M., 2015. NEURODEGENERATION. Alzheimer's and Parkinson's diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science 349 (6248), 1255555. Gotz, J., Chen, F., van Dorpe, J., Nitsch, R.M., 2001. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293 (5534), 1491e1495. Gunawardana, C.G., Mehrabian, M., Wang, X., Mueller, I., Lubambo, I.B., Jonkman, J.E., Wang, H., Schmitt-Ulms, G., 2015. The human tau interactome: binding to the ribonucleoproteome, and impaired binding of the proline-to-leucine mutant at position 301 (P301L) to chaperones and the proteasome. Molecular cell. Proteom.: MCP 14 (11), 3000e3014. Hock, C., Konietzko, U., Papassotiropoulos, A., Wollmer, A., Streffer, J., von Rotz, R.C., Davey, G., Moritz, E., Nitsch, R.M., 2002. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat. Med. 8 (11), 1270e1275. Iqbal, K., Liu, F., Gong, C.X., 2016. Tau and neurodegenerative disease: the story so far. Nature reviews. Neurology 12 (1), 15e27. Iwata, N., Tsubuki, S., Takaki, Y., Shirotani, K., Lu, B., Gerard, N.P., Gerard, C., Hama, E., Lee, H.J., Saido, T.C., 2001. Metabolic regulation of brain Abeta by neprilysin. Science 292 (5521), 1550e1552. Iwata, N., Tsubuki, S., Takaki, Y., Watanabe, K., Sekiguchi, M., Hosoki, E., Kawashima-Morishima, M., Lee, H.J., Hama, E., Sekine-Aizawa, Y., Saido, T.C., 2000. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 6 (2), 143e150. Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., Ihara, Y., 1994. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13 (1), 45e53. Jack Jr., C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., Petersen, R.C., Trojanowski, J.Q., 2010. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet. Neurol. 9 (1), 119e128. Jonsson, T., Atwal, J.K., Steinberg, S., Snaedal, J., Jonsson, P.V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., Hoyte, K., Gustafson, A., Liu, Y., Lu, Y., Bhangale, T., Graham, R.R., Huttenlocher, J., Bjornsdottir, G., Andreassen, O.A., Jonsson, E.G., Palotie, A., Behrens, T.W., Magnusson, O.T., Kong, A., Thorsteinsdottir, U., Watts, R.J., Stefansson, K., 2012. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488 (7409), 96e99. Jung, J.I., Ladd, T.B., Kukar, T., Price, A.R., Moore, B.D., Koo, E.H., Golde, T.E., Felsenstein, K.M., 2013. Steroids as gamma-secretase modulators. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 27 (9), 3775e3785. Karran, E., Mercken, M., De Strooper, B., 2011. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10 (9), 698e712. Kennedy, M.E., Stamford, A.W., Chen, X., Cox, K., Cumming, J.N., Dockendorf, M.F., Egan, M., Ereshefsky, L., Hodgson, R.A., Hyde, L.A., Jhee, S., Kleijn, H.J., Kuvelkar, R., Li, W., Mattson, B.A., Mei, H., Palcza, J., Scott, J.D., Tanen, M., Troyer, M.D., Tseng, J.L., Stone, J.A., Parker, E.M., Forman, M.S., 2016. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer's disease patients. Sci. Transl. Med. 8 (363), 363 ra150. Kuhn, P.H., Wang, H., Dislich, B., Colombo, A., Zeitschel, U., Ellwart, J.W., Kremmer, E., Rossner, S., Lichtenthaler, S.F., 2010. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29 (17), 3020e3032. Lee, S.H., Le Pichon, C.E., Adolfsson, O., Gafner, V., Pihlgren, M., Lin, H., Solanoy, H., Brendza, R., Ngu, H., Foreman, O., Chan, R., Ernst, J.A., DiCara, D., Hotzel, I., Srinivasan, K., Hansen, D.V., Atwal, J., Lu, Y., Bumbaca, D., Pfeifer, A., Watts, R.J., Muhs, A., Scearce-Levie, K., Ayalon, G., 2016. Antibody-mediated targeting of tau in vivo does not require effector function and microglial engagement. Cell Rep. 16 (6), 1690e1700.
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
6
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
Lewis, J., Dickson, D.W., Lin, W.L., Chisholm, L., Corral, A., Jones, G., Yen, S.H., Sahara, N., Skipper, L., Yager, D., Eckman, C., Hardy, J., Hutton, M., McGowan, E., 2001. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293 (5534), 1487e1491. Luo, Y., Bolon, B., Kahn, S., Bennett, B.D., Babu-Khan, S., Denis, P., Fan, W., Kha, H., Zhang, J., Gong, Y., Martin, L., Louis, J.C., Yan, Q., Richards, W.G., Citron, M., Vassar, R., 2001. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat. Neurosci. 4 (3), 231e232. Mawuenyega, K.G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J.C., Yarasheski, K.E., Bateman, R.J., 2010. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330 (6012), 1774. Miller, B.C., Eckman, E.A., Sambamurti, K., Dobbs, N., Chow, K.M., Eckman, C.B., Hersh, L.B., Thiele, D.L., 2003. Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc. Natl. Acad. Sci. U. S. A. 100 (10), 6221e6226. Mullard, A., 2016. Pharma pumps up anti-tau Alzheimer pipeline despite first Phase III failure. Nat. Rev. Drug Discov. 15 (9), 591e592. Novak, P., Schmidt, R., Kontsekova, E., Zilka, N., Kovacech, B., Skrabana, R., Vince-Kazmerova, Z., Katina, S., Fialova, L., Prcina, M., Parrak, V., Dal-Bianco, P., Brunner, M., Staffen, W., Rainer, M., Ondrus, M., Ropele, S., Smisek, M., Sivak, R., Winblad, B., Novak, M., 2016. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet. Neurol. http://dx.doi.org/ 10.1016/S1474-4422(16)30331-3. PMID: 27955995. Ohki, Y., Higo, T., Uemura, K., Shimada, N., Osawa, S., Berezovska, O., Yokoshima, S., Fukuyama, T., Tomita, T., Iwatsubo, T., 2011. Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J. 30 (23), 4815e4824. Osenkowski, P., Ye, W., Wang, R., Wolfe, M.S., Selkoe, D.J., 2008. Direct and potent regulation of gamma-secretase by its lipid microenvironment. J. Biol. Chem. 283 (33), 22529e22540. Qiu, W.Q., Ye, Z., Kholodenko, D., Seubert, P., Selkoe, D.J., 1997. Degradation of amyloid beta-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J. Biol. Chem. 272 (10), 6641e6646. Reiman, E.M., Quiroz, Y.T., Fleisher, A.S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., Fagan, A.M., Shah, A.R., Alvarez, S., Arbelaez, A., Giraldo, M., AcostaBaena, N., Sperling, R.A., Dickerson, B., Stern, C.E., Tirado, V., Munoz, C., Reiman, R.A., Huentelman, M.J., Alexander, G.E., Langbaum, J.B., Kosik, K.S., Tariot, P.N., Lopera, F., 2012. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. Lancet. Neurol. 11 (12), 1048e1056. Roberson, E.D., Scearce-Levie, K., Palop, J.J., Yan, F., Cheng, I.H., Wu, T., Gerstein, H., Yu, G.Q., Mucke, L., 2007. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 316 (5825), 750e754. Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerriere, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M., Dubas, F., Frebourg, T., Campion, D., 2006. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38 (1), 24e26. Saido, T., Leissring, M.A., 2012. Proteolytic degradation of amyloid beta-protein. Cold Spring Harb. Perspect. Med. 2 (6), a006379. Saido, T.C., 2013. Metabolism of amyloid beta peptide and pathogenesis of Alzheimer's disease. Proceedings of the Japan Academy. Ser. B, Phys. Biol. Sci. 89 (7), 321e339. Saito, T., Iwata, N., Tsubuki, S., Takaki, Y., Takano, J., Huang, S.M., Suemoto, T., Higuchi, M., Saido, T.C., 2005. Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat. Med. 11 (4), 434e439. Salloway, S., Sperling, R., Fox, N.C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L.S., Porsteinsson, A.P., Ferris, S., Reichert, M., Ketter, N., Nejadnik, B., Guenzler, V., Miloslavsky, M., Wang, D., Lu, Y., Lull, J., Tudor, I.C., Liu, E., Grundman, M., Yuen, E., Black, R., Brashear, H.R., Bapineuzumab, Clinical Trial, I., 2014. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370 (4), 322e333. Selkoe, D.J., Hardy, J., 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8 (6), 595e608. Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P.H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O'Gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M.S., Quintero-Monzon, O., Scannevin, R.H., Arnold, H.M., Engber, T., Rhodes, K., Ferrero, J., Hang, Y., Mikulskis, A., Grimm, J., Hock, C., Nitsch, R.M., Sandrock, A., 2016. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature 537 (7618), 50e56. Shamseddine, A.A., Airola, M.V., Hannun, Y.A., 2015. Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes. Adv. Biol. Regul. 57, 24e41. Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.F., Bruni, A.C., Montesi, M.P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R.J., Wasco, W., Da Silva, H.A., Haines, J.L., Perkicak-Vance, M.A., Tanzi, R.E., Roses, A.D., Fraser, P.E., Rommens, J.M., St George-Hyslop, P.H., 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375 (6534), 754e760. Shibata, M., Yamada, S., Kumar, S.R., Calero, M., Bading, J., Frangione, B., Holtzman, D.M., Miller, C.A., Strickland, D.K., Ghiso, J., Zlokovic, B.V., 2000. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Investigation 106 (12), 1489e1499. Shropshire, T.D., Reifert, J., Rajagopalan, S., Baker, D., Feinstein, S.C., Daugherty, P.S., 2014. Amyloid beta peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Abeta-mediated toxicity in vitro. Biol. Chem. 395 (1), 109e118. Sperling, R., Mormino, E., Johnson, K., 2014. The evolution of preclinical Alzheimer's disease: implications for prevention trials. Neuron 84 (3), 608e622. Takasugi, N., Sasaki, T., Ebinuma, I., Osawa, S., Isshiki, H., Takeo, K., Tomita, T., Iwatsubo, T., 2013. FTY720/fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. PloS one 8 (5), e64050. Takasugi, N., Sasaki, T., Shinohara, M., Iwatsubo, T., Tomita, T., 2015. Synthetic ceramide analogues increase amyloid-beta 42 production by modulating gamma-secretase activity. Biochem. Biophys. Res. Commun. 457 (2), 194e199. Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., Iwatsubo, T., 2003. The role of presenilin cofactors in the gamma-secretase complex. Nature 422 (6930), 438e441. Takeo, K., Tanimura, S., Shinoda, T., Osawa, S., Zahariev, I.K., Takegami, N., Ishizuka-Katsura, Y., Shinya, N., Takagi-Niidome, S., Tominaga, A., Ohsawa, N., Kimura-Someya, T., Shirouzu, M., Yokoshima, S., Yokoyama, S., Fukuyama, T., Tomita, T., Iwatsubo, T., 2014. Allosteric regulation of gamma-secretase activity by a phenylimidazole-type gamma-secretase modulator. Proc. Natl. Acad. Sci. U. S. A. 111 (29), 10544e10549. Tomita, T., 2014. Molecular mechanism of intramembrane proteolysis by gamma-secretase. J. Biochem. 156 (4), 195e201. Tomita, T., Maruyama, K., Saido, T.C., Kume, H., Shinozaki, K., Tokuhiro, S., Capell, A., Walter, J., Grunberg, J., Haass, C., Iwatsubo, T., Obata, K., 1997. The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Sci. U. S. A. 94 (5), 2025e2030. Yamada, K., Yabuki, C., Seubert, P., Schenk, D., Hori, Y., Ohtsuki, S., Terasaki, T., Hashimoto, T., Iwatsubo, T., 2009. Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. J. Neurosci. : Official J. Soc. Neurosci. 29 (36), 11393e11398. Yan, R., 2016. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl. Neurodegener. 5, 13. Yan, R., Vassar, R., 2014. Targeting the beta secretase BACE1 for Alzheimer's disease therapy. Lancet. Neurol. 13 (3), 319e329. Yang, Y.R., Kang, D.S., Lee, C., Seok, H., Follo, M.Y., Cocco, L., Suh, P.G., 2016. Primary phospholipase C and brain disorders. Adv. Biol. Regul. 61, 80e85. Yang, Y.R., Suh, P.G., 2014. O-GlcNAcylation in cellular functions and human diseases. Adv. Biol. Regul. 54, 68e73. Yuzwa, S.A., Shan, X., Macauley, M.S., Clark, T., Skorobogatko, Y., Vosseller, K., Vocadlo, D.J., 2012. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat. Chem. Biol. 8 (4), 393e399. Zhao, X., Kotilinek, L.A., Smith, B., Hlynialuk, C., Zahs, K., Ramsden, M., Cleary, J., Ashe, K.H., 2016. Caspase-2 cleavage of tau reversibly impairs memory. Nat. Med. 22 (11), 1268e1276.
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
Contents lists available at ScienceDirect
Advances in Biological Regulation journal homepage: www.elsevier.com/locate/jbior
Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease Taisuke Tomita* Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 December 2016 Received in revised form 24 December 2016 Accepted 4 January 2017 Available online xxx
Amyloid-b peptide (Ab) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Ab is derived from amyloid-b precursor protein that is sequentially cleaved by two aspartate proteases, b- and g-secretases. Secreted Ab is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Ab by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, the dynamics of cerebral Ab, called as “Ab economy”, would be the mechanistic basis of AD pathogenesis. Partial loss of g-secretase activity leads to the increased generation of toxic Ab isoforms, indicating that activation of g-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a b-secretase enzyme, has emerged as a prime drug target for lowering brain Ab levels. Recent studies revealed the decreased clearance of Ab in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Ab economy, and development of effective treatment and diagnostics for AD. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Alzheimer disease Amyloid-b peptide Membrane protein Protease Secretase Degradation
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proteolytic processing of APP by b- and g-secretases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of b- and g-secretase activities as a potential therapeutic strategy . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic approaches based on Ab degradation pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Permission note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
00 00 00 00 00 00 00 00 00
* Corresponding author. Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jbior.2017.01.001 2212-4926/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
2
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
1. Introduction Alzheimer disease (AD) is characterized by extensive neuronal loss and the appearance of two types of neuropathological hallmarks; senile plaques and neurofibrillary tangles (Goedert, 2015; Selkoe and Hardy, 2016; Sperling et al., 2014). Senile plaques present extracellularly and consist mainly of amyloid-b protein (Ab). Ab is produced from its precursor called amyloid precursor protein (APP) through sequential cleavage by b- and g-secretases (De Strooper et al., 2010) (Fig. 1). Neurofibrillary tangles are comprised of intraneuronal aggregation of microtubule-binding protein, tau. Importantly, genetic mutations in APP gene found in patients of the dominantly inherited form of familial AD cause increased production and/or aggregation of Ab (Selkoe and Hardy, 2016). Moreover, genes encoding multipass membrane proteins called presenilin (PS) 1 and 2 were identified in familial AD patients (Sherrington et al., 1995). These mutations alter the g-secretase-mediated cleavage of APP, leading to increased production of the more aggregation-prone form of Ab (Borchelt et al., 1996; Tomita et al., 1997). APP locus duplication was also identified in autosomal dominant early-onset AD cases (Rovelet-Lecrux et al., 2006). And recently, a rare coding mutation A673T in the APP gene that reduces the b-secretase-mediated cleavage has been identified in the elderly without AD as a protective allele (Jonsson et al., 2012), supporting the central role of Ab in the development of AD. In contrast, aberrant tau aggregates are present not only in AD, but several neurodegenerative disease such as progressive supranuclear palsy, Pick's disease, corticobasal degeneration or frontotemporal dementia, the latter being characterized by massive neuronal loss and the formation of tangles without deposition of Ab (Iqbal et al., 2016). Tau is a phosphoprotein that promotes the assembly and stabilization of microtubules. Tau also interacts with several proteins such as phospholipase C to regulate intracellular signaling involved in the neuronal functions (Gunawardana et al., 2015; Yang et al., 2016). Aggregated tau undergoes hyperphosphorylation, which promotes dissociation of tau from the microtubules and self-aggregation. Importantly, mutations in tau gene are linked to autosomal dominant form of frontotemporal dementia, indicating that tau pathology correlates with neuronal death. In fact, biomarker observational studies suggest a pathological model of AD that brain Ab deposits early, before neurodegeneration biomarker changes (i.e., brain atrophy and increased cerebrospinal fluid (CSF) tau) and clinical symptoms occur (Jack et al., 2010). Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant familial AD patients also support this model (Bateman et al., 2012; Reiman et al., 2012). Finally, tangle pathology was induced/exacerbated by aggregated Ab in model animals (Gotz et al., 2001; Lewis et al., 2001), and tau was required for the Ab mediated neurotoxicity (Roberson et al., 2007). Thus, these observations clearly suggest that Ab is an initiator molecule of AD pathogenesis, and tau is associated with neuronal dysfunction and cell death (Sperling et al., 2014). 2. Proteolytic processing of APP by b- and g-secretases APP is processed by the non-amyloidogenic or amyloidogenic pathway (De Strooper et al., 2010). In the non-amyloidogenic pathway, APP is first cleaved at its juxtamembrane region by a-secretase, leading to generation of the soluble N-terminal fragment sAPPa and C-terminal stub called C83. A disintegrin and metalloprotease 10 (ADAM10) is the main enzyme responsible for a-secretase activity (Kuhn et al., 2010). In the amyloidogenic pathway, b-site APP-cleaving enzyme 1 (BACE1) endoproteolyzes APP at ectodomain, yielding the secreted sAPPb and a longer C-terminal fragment, C99 (Yan, 2016; Yan and Vassar, 2014). Then both C83 and C99 are subjected to intramembrane cleavage by g-secretase to release extracellularly p3 or Ab, respectively. As BACE1 is a single-span membrane-anchored aspartic protease expressed in neuronal cells, Ab is mainly generated from neurons. g-Secretase-mediated cleavage occurs several cell types, and generates heterogeneity in the Cterminal length of Ab, mainly producing Ab40 and Ab42. Ab42 is the most toxic and aggregation-prone Ab species and is the predominant species deposited in AD brains (Iwatsubo et al., 1994). Notably, it took about 10 years to gain a comprehensive understanding of g-cleavage at molecular level, because the g-secretase mediated hydrolysis of APP should be occurred within the transmembrane domain (TMD) that is embedded in the hydrophobic environment. Several biochemical, cell
Fig. 1. Schematic diagram of proteolytic processing of APP and Ab. b-Secretase/BACE1 cleaves APP to generate sAPPb and C99, the latter being further processed by g-secretase. These sequential cleavages result in the production of Ab, which is a main component of the senile plaque. The minimal g-secretase complex is comprised of PS, nicastrin, Aph-1 and Pen-2. Ab is then metabolized by proteolytic processing by Ab-degrading enzymes and other catabolic processes (i.e., phagocytosis, passive and active transport, diffusion).
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
3
biological and genetic studies now revealed that g-secretase is a membrane complex comprised of PS, nicastrin, Aph-1 and Pen-2, and PS is the catalytic molecule responsible for g-secretase-mediated intramembrane cleavage (Takasugi et al., 2003; Tomita, 2014). And recently, the atomic structure of human g-secretase complex was resolved by single-particle cryo-electron microscopy (Bai et al., 2015). Catalytic aspartates are faced to hydrophilic cavity in the PS formed within the lipid bilayer, supporting a notion that PS itself executes intramembrane proteolysis. 3. Regulation of b- and g-secretase activities as a potential therapeutic strategy With regard to the development of AD therapeutics, lowering Ab production by inhibition of b- or g-secretase activity has been a prime strategy. In fact, several cell-permeable g-secretase inhibitors have been identified by cell-based screening and combinatorial chemistry. However, these g-secretase inhibitors block the cleavage of not only APP but other g-secretase substrates, including notch receptor that plays an important role in developmental process and maintenance of stem cells. Indeed, a phase 3 trial of semagacestat from Eli Lilly was discontinued because of increased incidences of skin cancer and worsening of cognitive function (Doody et al., 2013). Clinical trial of different g-secretase inhibitor, avagacestat from BristolMyers-Squibb, was also halted because of similar adverse effects (Amanatkar et al., 2016), suggesting that the development of g-secretase inhibitors as AD therapeutics is difficult. Other compounds called g-secretase modulators (GSMs) have been highlighted to alter Ab production without affecting notch signaling (Crump et al., 2013). GSMs only shift the production away from the aggregation-prone longer Ab species, increasing the production of the shorter Ab species. Phase 3 trial of a first generation Ab42-lowering GSM, R-Flurbiprofen (tarenflurbil), was terminated because it failed to achieve a significant therapeutic effect. Currently, second generation GSMs with a phenylimidazole backbone have been tested in clinical trials. Intriguingly, the g-secretase activity is also modulated by endogenous lipids and their analogues (e.g., steroids, sphingolipids, ceramide) (Jung et al., 2013; Osenkowski et al., 2008; Takasugi et al., 2013, 2015). Thus, enzymes involved in the metabolism of these lipids would be novel targets for the modulation of the g-secretase activity, Ab production and brain Ab economy (Fonseca et al., 2010; Shamseddine et al., 2015). Regarding the molecular mechanisms of the synthetic GSMs, we have recently revealed that these compounds directly target to PS to allosterically activate the g-secretase activity using chemical biology approaches (Ohki et al., 2011; Takeo et al., 2014). Moreover, artificial genetic mutations in PS1 that activates g-secretase activity reduce Ab42 production in mammalian cells (Futai et al., 2016). Supporting this notion, familial AD-linked mutations in PS1 that overproduce Ab42 causes a partial loss-of-function in the enzymatic activity of g-secretase (Chavez-Gutierrez et al., 2012). Thus, development of small compounds that activate, but not inhibit, the g-secretase activity using the detailed structural information of g-secretase would pave the way for the development of novel efficient AD therapy. BACE1 knockout mice crossed with APP transgenic mice do not produce Ab, nor show Ab deposition in the brain, suggesting the critical role of BACE1 in Ab amyloidosis (Cai et al., 2001; Luo et al., 2001). Genetic finding of protective allele in non-demented individuals that reduce b-cleavage also support the notion that inhibition of BACE1 activity is a promising strategy against AD (Yan and Vassar, 2014). However, because of the largely open catalytic site structure, drug development of BACE1 inhibitor has proven challenging (Ghosh and Osswald, 2014). After intense efforts in both academia and industry, several BACE1 inhibitors have recently entered human clinical trials. Verubecestat (MK-8931) from Merck Research Laboratories is a potent and selective BACE1 inhibitor that reduced brain concentrations of Ab in rats, monkeys and human subjects (Kennedy et al., 2016). Recently, AstraZeneca and Eli Lilly announced joint development of AZD-3293, which is a potent BACE1 inhibitor and successfully decreased the CSF Ab in human healthy volunteers, in 5-year phase II/III trial. In addition to them, JNJ-54861911 from Janssen/Shionogi, E2609 from Eisai/Biogen, and CNP520 from Novartis/Amgen have been under development as AD therapeutics (Yan, 2016). 4. Therapeutic approaches based on Ab degradation pathway In brain, soluble form of Ab is rapidly eliminated with a half-life of ~30 min (Shibata et al., 2000; Yamada et al., 2009), suggesting that Ab is actively degraded. Thus, the homeostatic balance of production and degradation of Ab, denoted as Ab economy, is a critical determinant for brain Ab levels (Karran et al., 2011) (Fig. 2). Moreover, Mawuenyega and colleagues observed decreased clearance rather than increased production of Ab in the CSF of sporadic AD patients (Mawuenyega et al., 2010). Thus, in addition to overproduction of Ab, decreased Ab degradation would lead to aberrant brain Ab economy and underlie the pathogenic mechanism of AD. However, whole picture of Ab catabolism in brain still remains unclear. In vitro studies revealed that Ab is degraded by several proteases with diverse characteristics (Saido and Leissring, 2012; Saido, 2013). Among them, neprilysin (Iwata et al., 2000) and insulin-degrading enzyme (IDE) (Qiu et al., 1997) are well-established Abdegrading enzymes that has been extensively investigated for its role in the regulation of brain Ab level in vitro and in vivo. Brains of KO mice of these proteases showed 1.4e2 fold increase in brain Ab levels (Farris et al., 2003; Iwata et al., 2001; Miller et al., 2003). Moreover, transgenic overexpression of either neprilysin or IDE reduces the amyloid pathology in vivo, suggesting that each protease is a rate limiting enzyme in the determination of cerebral Ab concentrations. In fact, enzymatic character and molecular nature of these peptidases are distinct. Neprilysin is a single span membrane associated metalloprotease expressed in neurons, not in glia, and axonally transported to presynaptic terminals (Fukami et al., 2002). Notably, somatostatin upregulated neprilysin activity in primary cortical neurons, suggesting that somatostatin pathway is a pharmacological-target for AD therapeutics based on the upregulation of neprilysin activity (Saito et al., 2005). IDE is also zinc-metalloprotease, but present in both cytosol and extracellular space, whereas IDE lacks a conventional signal sequence. Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
4
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
Fig. 2. Altered brain Ab economy in the AD pathogenesis. Brain Ab economy is regulated by the rates of Ab production and degradation/clearance. Note that almost all genetic mutations/variations found in autosomal dominant familial AD cases (FAD) affect the production or aggregation of Ab. In contrast, decreased Ab clearance rate is implicated in the sporadic AD cases (SAD). Both alterations cause the increase in the soluble Ab level and aggregability, thereby leading the deposition of Ab as senile plaques.
IDE is expressed variety of cell lines including microglia. However, as insulin is a better endogenous substrate than Ab for IDE, altered insulin signaling would be presumed by upregulation of IDE expression and/or activity. Of note, neither neprilysin nor IDE can degrade the fibrillar Ab, indicating that aggregation status of Ab peptides also impacts on the Ab economy regulated by these peptidases. Recently, we have identified kallikrein-related peptidase 7 (KLK7) as a novel Ab-degrading enzyme secreted the astrocytes (Kidana, Tatebe, Tomita et al., unpublished data). Notably, KLK7 is able to cleave fibrillar form of Ab and attenuate its cell toxicity in primary neuronal culture (Shropshire et al., 2014), suggesting the importance of KLK7 in the development of amyloid pathology. Moreover, expression level of KLK7 was significantly reduced in the sporadic AD patients (Diamandis et al., 2004). Thus, upregulation of KLK7 would provide beneficial effect for individuals who has already developed the senile plaques. 5. Conclusions Advances in genetics and clinically relevant sequencing applications have provided important information of aberrant Ab production machinery (i.e., altered b- and g-secretase-mediated cleavages) in the pathomechanism of familial AD. Based on these observations, large phase II/III trials of b-secretase inhibitor are currently ongoing. In addition, antibody-mediated clearance of Ab has been tested in clinical trials, although the efficacies of antibody drugs on the amyloid pathology and neurological symptoms were varied (Doody et al., 2014; Hock et al., 2002; Salloway et al., 2014; Sevigny et al., 2016). Thus, pharmacological stimulation of Ab-degrading activity would provide the different approach to modify brain Ab economy. However, it still remains unknown why Ab is deposited in the sporadic AD cases, in which decreased Ab clearance was implicated. One possibility is that aging affects the catabolic mechanism of Ab in the brain. In fact, age-dependent Ab accumulation in the brains of nondemented elderly precedes the formation of senile plaques (Funato et al., 1998). It would be intriguing whether the proteolytic activity of physiological Ab degrading enzyme(s) declines in cognitively normal elderly. To do this, identification of reliable surrogate biomarker that reflects the Ab-degrading activity in the brain is needed. In addition to Ab, development of tau-targeted therapeutics (e.g., vaccination (Novak et al., 2016), anti-tau antibody (Lee et al., 2016), inhibition of O-GlcNAcylation (Yang and Suh, 2014; Yuzwa et al., 2012)) has been highlighted (Iqbal et al., 2016; Mullard, 2016). Notably, several proteases have been implicated in the tau toxicity (Chesser et al., 2013; Zhao et al., 2016). Nevertheless, further researches on these proteolytic mechanisms may provide new promising therapeutic/prevention strategies for AD. Conflict of interest The author declares no competing financial interests. Permission note All material in the manuscript is original contents. Acknowledgements This work was supported in part by a Grant-in-Aid for Scientific Research (A) [15H02492] from the Japan Society for the Promotion of Science, Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development [16dm0107056h0001] and grant from the Pharmacological Research Foundation, Tokyo. Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
5
References Amanatkar, H.R., Papagiannopoulos, B., Grossberg, G.T., 2016. Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies. Expert Rev. Neurother. 1e10. Bai, X.C., Yan, C., Yang, G., Lu, P., Ma, D., Sun, L., Zhou, R., Scheres, S.H., Shi, Y., 2015. An atomic structure of human gamma-secretase. Nature 525 (7568), 212e217. Bateman, R.J., Xiong, C., Benzinger, T.L., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Cairns, N.J., Xie, X., Blazey, T.M., Holtzman, D.M., Santacruz, A., Buckles, V., Oliver, A., Moulder, K., Aisen, P.S., Ghetti, B., Klunk, W.E., McDade, E., Martins, R.N., Masters, C.L., Mayeux, R., Ringman, J.M., Rossor, M.N., Schofield, P.R., Sperling, R.A., Salloway, S., Morris, J.C., Dominantly Inherited Alzheimer, N., 2012. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367 (9), 795e804. Borchelt, D.R., Thinakaran, G., Eckman, C.B., Lee, M.K., Davenport, F., Ratovitsky, T., Prada, C.M., Kim, G., Seekins, S., Yager, D., Slunt, H.H., Wang, R., Seeger, M., Levey, A.I., Gandy, S.E., Copeland, N.G., Jenkins, N.A., Price, D.L., Younkin, S.G., Sisodia, S.S., 1996. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17 (5), 1005e1013. Cai, H., Wang, Y., McCarthy, D., Wen, H., Borchelt, D.R., Price, D.L., Wong, P.C., 2001. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat. Neurosci. 4 (3), 233e234. Chavez-Gutierrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., Wiltfang, J., Serneels, L., Karran, E., Gijsen, H., Schymkowitz, J., Rousseau, F., Broersen, K., De Strooper, B., 2012. The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J. 31 (10), 2261e2274. Chesser, A.S., Pritchard, S.M., Johnson, G.V., 2013. Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease. Front. Neurol. 4, 122. Crump, C.J., Johnson, D.S., Li, Y.M., 2013. Development and mechanism of gamma-secretase modulators for Alzheimer's disease. Biochemistry 52 (19), 3197e3216. De Strooper, B., Vassar, R., Golde, T., 2010. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. reviews. Neurol. 6 (2), 99e107. Diamandis, E.P., Scorilas, A., Kishi, T., Blennow, K., Luo, L.Y., Soosaipillai, A., Rademaker, A.W., Sjogren, M., 2004. Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia. Clin. Biochem. 37 (3), 230e237. Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R.G., Aisen, P.S., , Alzheimer's Disease Cooperative Study Steering, C, Siemers, E., Sethuraman, G., Mohs, R., Semagacestat Study, G., 2013. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369 (4), 341e350. Doody, R.S., Thomas, R.G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P.S., Siemers, E., Liu-Seifert, H., Mohs, R., , Alzheimer's Disease Cooperative Study Steering, C, Solanezumab Study, G., 2014. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370 (4), 311e321. Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E.A., Frosch, M.P., Eckman, C.B., Tanzi, R.E., Selkoe, D.J., Guenette, S., 2003. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc. Natl. Acad. Sci. U. S. A. 100 (7), 4162e4167. Fonseca, A.C., Resende, R., Oliveira, C.R., Pereira, C.M., 2010. Cholesterol and statins in Alzheimer's disease: current controversies. Exp. Neurol. 223 (2), 282e293. Fukami, S., Watanabe, K., Iwata, N., Haraoka, J., Lu, B., Gerard, N.P., Gerard, C., Fraser, P., Westaway, D., St George-Hyslop, P., Saido, T.C., 2002. Abeta-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology. Neurosci. Res. 43 (1), 39e56. Funato, H., Yoshimura, M., Kusui, K., Tamaoka, A., Ishikawa, K., Ohkoshi, N., Namekata, K., Okeda, R., Ihara, Y., 1998. Quantitation of amyloid beta-protein (A beta) in the cortex during aging and in Alzheimer's disease. Am. J. Pathol. 152 (6), 1633e1640. Futai, E., Osawa, S., Cai, T., Fujisawa, T., Ishiura, S., Tomita, T., 2016. Suppressor mutations for presenilin 1 familial alzheimer disease mutants modulate gamma-secretase activities. J. Biol. Chem. 291 (1), 435e446. Ghosh, A.K., Osswald, H.L., 2014. BACE1 (beta-secretase) inhibitors for the treatment of Alzheimer's disease. Chem. Soc. Rev. 43 (19), 6765e6813. Goedert, M., 2015. NEURODEGENERATION. Alzheimer's and Parkinson's diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science 349 (6248), 1255555. Gotz, J., Chen, F., van Dorpe, J., Nitsch, R.M., 2001. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293 (5534), 1491e1495. Gunawardana, C.G., Mehrabian, M., Wang, X., Mueller, I., Lubambo, I.B., Jonkman, J.E., Wang, H., Schmitt-Ulms, G., 2015. The human tau interactome: binding to the ribonucleoproteome, and impaired binding of the proline-to-leucine mutant at position 301 (P301L) to chaperones and the proteasome. Molecular cell. Proteom.: MCP 14 (11), 3000e3014. Hock, C., Konietzko, U., Papassotiropoulos, A., Wollmer, A., Streffer, J., von Rotz, R.C., Davey, G., Moritz, E., Nitsch, R.M., 2002. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat. Med. 8 (11), 1270e1275. Iqbal, K., Liu, F., Gong, C.X., 2016. Tau and neurodegenerative disease: the story so far. Nature reviews. Neurology 12 (1), 15e27. Iwata, N., Tsubuki, S., Takaki, Y., Shirotani, K., Lu, B., Gerard, N.P., Gerard, C., Hama, E., Lee, H.J., Saido, T.C., 2001. Metabolic regulation of brain Abeta by neprilysin. Science 292 (5521), 1550e1552. Iwata, N., Tsubuki, S., Takaki, Y., Watanabe, K., Sekiguchi, M., Hosoki, E., Kawashima-Morishima, M., Lee, H.J., Hama, E., Sekine-Aizawa, Y., Saido, T.C., 2000. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 6 (2), 143e150. Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., Ihara, Y., 1994. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13 (1), 45e53. Jack Jr., C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., Petersen, R.C., Trojanowski, J.Q., 2010. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet. Neurol. 9 (1), 119e128. Jonsson, T., Atwal, J.K., Steinberg, S., Snaedal, J., Jonsson, P.V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., Hoyte, K., Gustafson, A., Liu, Y., Lu, Y., Bhangale, T., Graham, R.R., Huttenlocher, J., Bjornsdottir, G., Andreassen, O.A., Jonsson, E.G., Palotie, A., Behrens, T.W., Magnusson, O.T., Kong, A., Thorsteinsdottir, U., Watts, R.J., Stefansson, K., 2012. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488 (7409), 96e99. Jung, J.I., Ladd, T.B., Kukar, T., Price, A.R., Moore, B.D., Koo, E.H., Golde, T.E., Felsenstein, K.M., 2013. Steroids as gamma-secretase modulators. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 27 (9), 3775e3785. Karran, E., Mercken, M., De Strooper, B., 2011. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10 (9), 698e712. Kennedy, M.E., Stamford, A.W., Chen, X., Cox, K., Cumming, J.N., Dockendorf, M.F., Egan, M., Ereshefsky, L., Hodgson, R.A., Hyde, L.A., Jhee, S., Kleijn, H.J., Kuvelkar, R., Li, W., Mattson, B.A., Mei, H., Palcza, J., Scott, J.D., Tanen, M., Troyer, M.D., Tseng, J.L., Stone, J.A., Parker, E.M., Forman, M.S., 2016. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer's disease patients. Sci. Transl. Med. 8 (363), 363 ra150. Kuhn, P.H., Wang, H., Dislich, B., Colombo, A., Zeitschel, U., Ellwart, J.W., Kremmer, E., Rossner, S., Lichtenthaler, S.F., 2010. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29 (17), 3020e3032. Lee, S.H., Le Pichon, C.E., Adolfsson, O., Gafner, V., Pihlgren, M., Lin, H., Solanoy, H., Brendza, R., Ngu, H., Foreman, O., Chan, R., Ernst, J.A., DiCara, D., Hotzel, I., Srinivasan, K., Hansen, D.V., Atwal, J., Lu, Y., Bumbaca, D., Pfeifer, A., Watts, R.J., Muhs, A., Scearce-Levie, K., Ayalon, G., 2016. Antibody-mediated targeting of tau in vivo does not require effector function and microglial engagement. Cell Rep. 16 (6), 1690e1700.
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001
6
T. Tomita / Advances in Biological Regulation xxx (2016) 1e6
Lewis, J., Dickson, D.W., Lin, W.L., Chisholm, L., Corral, A., Jones, G., Yen, S.H., Sahara, N., Skipper, L., Yager, D., Eckman, C., Hardy, J., Hutton, M., McGowan, E., 2001. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293 (5534), 1487e1491. Luo, Y., Bolon, B., Kahn, S., Bennett, B.D., Babu-Khan, S., Denis, P., Fan, W., Kha, H., Zhang, J., Gong, Y., Martin, L., Louis, J.C., Yan, Q., Richards, W.G., Citron, M., Vassar, R., 2001. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat. Neurosci. 4 (3), 231e232. Mawuenyega, K.G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J.C., Yarasheski, K.E., Bateman, R.J., 2010. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330 (6012), 1774. Miller, B.C., Eckman, E.A., Sambamurti, K., Dobbs, N., Chow, K.M., Eckman, C.B., Hersh, L.B., Thiele, D.L., 2003. Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc. Natl. Acad. Sci. U. S. A. 100 (10), 6221e6226. Mullard, A., 2016. Pharma pumps up anti-tau Alzheimer pipeline despite first Phase III failure. Nat. Rev. Drug Discov. 15 (9), 591e592. Novak, P., Schmidt, R., Kontsekova, E., Zilka, N., Kovacech, B., Skrabana, R., Vince-Kazmerova, Z., Katina, S., Fialova, L., Prcina, M., Parrak, V., Dal-Bianco, P., Brunner, M., Staffen, W., Rainer, M., Ondrus, M., Ropele, S., Smisek, M., Sivak, R., Winblad, B., Novak, M., 2016. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet. Neurol. http://dx.doi.org/ 10.1016/S1474-4422(16)30331-3. PMID: 27955995. Ohki, Y., Higo, T., Uemura, K., Shimada, N., Osawa, S., Berezovska, O., Yokoshima, S., Fukuyama, T., Tomita, T., Iwatsubo, T., 2011. Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J. 30 (23), 4815e4824. Osenkowski, P., Ye, W., Wang, R., Wolfe, M.S., Selkoe, D.J., 2008. Direct and potent regulation of gamma-secretase by its lipid microenvironment. J. Biol. Chem. 283 (33), 22529e22540. Qiu, W.Q., Ye, Z., Kholodenko, D., Seubert, P., Selkoe, D.J., 1997. Degradation of amyloid beta-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J. Biol. Chem. 272 (10), 6641e6646. Reiman, E.M., Quiroz, Y.T., Fleisher, A.S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., Fagan, A.M., Shah, A.R., Alvarez, S., Arbelaez, A., Giraldo, M., AcostaBaena, N., Sperling, R.A., Dickerson, B., Stern, C.E., Tirado, V., Munoz, C., Reiman, R.A., Huentelman, M.J., Alexander, G.E., Langbaum, J.B., Kosik, K.S., Tariot, P.N., Lopera, F., 2012. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. Lancet. Neurol. 11 (12), 1048e1056. Roberson, E.D., Scearce-Levie, K., Palop, J.J., Yan, F., Cheng, I.H., Wu, T., Gerstein, H., Yu, G.Q., Mucke, L., 2007. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 316 (5825), 750e754. Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerriere, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M., Dubas, F., Frebourg, T., Campion, D., 2006. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38 (1), 24e26. Saido, T., Leissring, M.A., 2012. Proteolytic degradation of amyloid beta-protein. Cold Spring Harb. Perspect. Med. 2 (6), a006379. Saido, T.C., 2013. Metabolism of amyloid beta peptide and pathogenesis of Alzheimer's disease. Proceedings of the Japan Academy. Ser. B, Phys. Biol. Sci. 89 (7), 321e339. Saito, T., Iwata, N., Tsubuki, S., Takaki, Y., Takano, J., Huang, S.M., Suemoto, T., Higuchi, M., Saido, T.C., 2005. Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat. Med. 11 (4), 434e439. Salloway, S., Sperling, R., Fox, N.C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L.S., Porsteinsson, A.P., Ferris, S., Reichert, M., Ketter, N., Nejadnik, B., Guenzler, V., Miloslavsky, M., Wang, D., Lu, Y., Lull, J., Tudor, I.C., Liu, E., Grundman, M., Yuen, E., Black, R., Brashear, H.R., Bapineuzumab, Clinical Trial, I., 2014. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370 (4), 322e333. Selkoe, D.J., Hardy, J., 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8 (6), 595e608. Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P.H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O'Gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M.S., Quintero-Monzon, O., Scannevin, R.H., Arnold, H.M., Engber, T., Rhodes, K., Ferrero, J., Hang, Y., Mikulskis, A., Grimm, J., Hock, C., Nitsch, R.M., Sandrock, A., 2016. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature 537 (7618), 50e56. Shamseddine, A.A., Airola, M.V., Hannun, Y.A., 2015. Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes. Adv. Biol. Regul. 57, 24e41. Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.F., Bruni, A.C., Montesi, M.P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R.J., Wasco, W., Da Silva, H.A., Haines, J.L., Perkicak-Vance, M.A., Tanzi, R.E., Roses, A.D., Fraser, P.E., Rommens, J.M., St George-Hyslop, P.H., 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375 (6534), 754e760. Shibata, M., Yamada, S., Kumar, S.R., Calero, M., Bading, J., Frangione, B., Holtzman, D.M., Miller, C.A., Strickland, D.K., Ghiso, J., Zlokovic, B.V., 2000. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Investigation 106 (12), 1489e1499. Shropshire, T.D., Reifert, J., Rajagopalan, S., Baker, D., Feinstein, S.C., Daugherty, P.S., 2014. Amyloid beta peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Abeta-mediated toxicity in vitro. Biol. Chem. 395 (1), 109e118. Sperling, R., Mormino, E., Johnson, K., 2014. The evolution of preclinical Alzheimer's disease: implications for prevention trials. Neuron 84 (3), 608e622. Takasugi, N., Sasaki, T., Ebinuma, I., Osawa, S., Isshiki, H., Takeo, K., Tomita, T., Iwatsubo, T., 2013. FTY720/fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. PloS one 8 (5), e64050. Takasugi, N., Sasaki, T., Shinohara, M., Iwatsubo, T., Tomita, T., 2015. Synthetic ceramide analogues increase amyloid-beta 42 production by modulating gamma-secretase activity. Biochem. Biophys. Res. Commun. 457 (2), 194e199. Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., Iwatsubo, T., 2003. The role of presenilin cofactors in the gamma-secretase complex. Nature 422 (6930), 438e441. Takeo, K., Tanimura, S., Shinoda, T., Osawa, S., Zahariev, I.K., Takegami, N., Ishizuka-Katsura, Y., Shinya, N., Takagi-Niidome, S., Tominaga, A., Ohsawa, N., Kimura-Someya, T., Shirouzu, M., Yokoshima, S., Yokoyama, S., Fukuyama, T., Tomita, T., Iwatsubo, T., 2014. Allosteric regulation of gamma-secretase activity by a phenylimidazole-type gamma-secretase modulator. Proc. Natl. Acad. Sci. U. S. A. 111 (29), 10544e10549. Tomita, T., 2014. Molecular mechanism of intramembrane proteolysis by gamma-secretase. J. Biochem. 156 (4), 195e201. Tomita, T., Maruyama, K., Saido, T.C., Kume, H., Shinozaki, K., Tokuhiro, S., Capell, A., Walter, J., Grunberg, J., Haass, C., Iwatsubo, T., Obata, K., 1997. The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Sci. U. S. A. 94 (5), 2025e2030. Yamada, K., Yabuki, C., Seubert, P., Schenk, D., Hori, Y., Ohtsuki, S., Terasaki, T., Hashimoto, T., Iwatsubo, T., 2009. Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. J. Neurosci. : Official J. Soc. Neurosci. 29 (36), 11393e11398. Yan, R., 2016. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl. Neurodegener. 5, 13. Yan, R., Vassar, R., 2014. Targeting the beta secretase BACE1 for Alzheimer's disease therapy. Lancet. Neurol. 13 (3), 319e329. Yang, Y.R., Kang, D.S., Lee, C., Seok, H., Follo, M.Y., Cocco, L., Suh, P.G., 2016. Primary phospholipase C and brain disorders. Adv. Biol. Regul. 61, 80e85. Yang, Y.R., Suh, P.G., 2014. O-GlcNAcylation in cellular functions and human diseases. Adv. Biol. Regul. 54, 68e73. Yuzwa, S.A., Shan, X., Macauley, M.S., Clark, T., Skorobogatko, Y., Vosseller, K., Vocadlo, D.J., 2012. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat. Chem. Biol. 8 (4), 393e399. Zhao, X., Kotilinek, L.A., Smith, B., Hlynialuk, C., Zahs, K., Ramsden, M., Cleary, J., Ashe, K.H., 2016. Caspase-2 cleavage of tau reversibly impairs memory. Nat. Med. 22 (11), 1268e1276.
Please cite this article in press as: Tomita, T., Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease, Advances in Biological Regulation (2016), http://dx.doi.org/10.1016/j.jbior.2017.01.001