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Immunotherapy for Alzheimer's disease: attacking amyloid-β from the inside
Update
TRENDS in Immunology
Vol.28 No.12
Research Focus
Immunotherapy for Alzheimer’s disease: attacking amyloid-b from the inside Michal Arbel and Beka Solomon Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv 69978, Israel
Although extracellular Ab plaques are a hallmark of Alzheimer’s disease, it remains to be determined whether extracellular or intracellular Ab accumulation initiates the disease process. A recent paper from Gunnar Gouras’ group showed that Ab antibodies lead to reduced intracellular Ab levels in neurons via antibody internalization after binding to the Ab domain of amyloid precursor protein (APP) at the plasma membrane. This work suggests novel avenues for the immunotherapy of Alzheimer’s disease. Alzheimer’s disease (AD) is a progressive neurodegeneration and the most common form of dementia in the elderly. The disease is characterized by massive cell loss, especially of cholinergic neurons; deposition of fibrillar amyloid-b (Ab) peptides as senile plaques; and intracellular accumulation of hyperphosphorylated tau protein as neurofibrillary tangles [1]. Although AD pathogenesis is complex and remains unclear, aggregation of Ab peptides is considered to be the first known event in a complex cascade eventually leading to neurodegeneration [2]. Emerging evidences that will be discussed below suggest a pivotal role for intracellular Ab accumulation in the early stages of AD pathogenesis. Antibodies against Ab peptides are effective in reducing Ab levels and plaque pathology, as well as attenuating cognitive deficits in AD animal models (reviewed in [3]). Passive and active Ab immunizations of the AD triple transgenic mice model (3 Tg), which overexpress mutated amyloid precursor protein (APP)-, Presenilin 1 (PS1)-, and tau-encoding genes, led to reduction of both extracellular and intracellular Ab levels, with the latter correlated with cognitive improvement [4,5]. Despite the fact that the extracellular Ab plaques are a hallmark of AD and are considered criteria for an ultimate postmortem diagnosis of the disease, it is yet to be determined whether extracellular Ab deposition or intracellular Ab accumulation initiates the disease process. Three distinct mechanisms (discussed in Box 1) have been suggested for antibody-mediated clearance of the extracellular Ab deposits. Unlike the mechanisms suggested for the extracellular Ab reduction, the mechanism by which anti-Ab antibodies affect intracellular Ab is unclear. A recent paper by Gouras and colleagues offered an interesting, novel mechanism by which Corresponding author: Solomon, B. ([email protected]). Available online 5 November 2007. www.sciencedirect.com
anti-Ab antibodies mediate intraneuronal Ab reduction [6]. To investigate the mechanism by which anti-Ab antibodies mediate the intracellular Ab reduction, Tampellini et al. [6] performed an extensive work and employed both a neuronal cell line and primary neurons extracted from the Tg2576 AD transgenic mice model. This work provides evidence that anti-Ab antibodies reduce intracellular Ab levels in cultured neurons and protect against synaptic dysfunction. Utilizing 6E10 and 4G8 antibodies, which are directed to the N terminus and mid-region of Ab, respectively, the authors showed that the antibodies are internalized into the cells by binding to the Ab sequence of the APP molecule. Antibody internalization via endocytosis is required, yet alone insufficient, for intracellular Ab reduction, as evidenced by APP N terminus antibody, which internalizes into the cells in a similar manner to Ab antibodies, but did not alter Ab levels. These results suggest that antibody-mediated reduction in Ab levels relies on its binding to the Ab sequence of APP. Importantly, Ab C-terminal specific antibody, which does not bind APP, failed to enter the cells and affect intracellular Ab levels. The authors excluded an increase in Ab secretion and decreased processing of APP by both band g-secretase as possible mechanisms for Ab clearance. Interestingly, the related products of b-secretase cleavage C99 and soluble bAPP were elevated, suggesting that antibody internalization after APP binding in fact promotes b-secretase cleavage. Finally, the authors further propose a scenario in which anti-Ab antibodies accelerate APP internalization into the early endosomes, where increased BACE1 (b-secretase) cleavage occurs, followed by an enhanced degradation of the cleavage products (Ab and C99) through the endosomal and lysosomal pathways. These steps are illustrated in Figure 1. The results in this study support our previously reported data regarding antibody directed to the b-secretase cleavage site of the APP molecule (b-site) in spite of the fact that this antibody does not bind any form of Ab [7]. Anti-b-site antibody was shown to internalize into the cell after APP binding at the plasma membrane and to significantly reduce intracellular Ab levels. The trafficking of anti-b-site antibody is similar to that reported for Ab antibodies by the Gouras group; anti-b-site antibody is colocalized with an early endosome marker starting at 2 min after incubation and is evident at the lysosomes at later time points (from 45 min and later; unpublished data). Inconsistent with their results, intracellular Ab
1471-4906/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2007.09.005
512
Update
TRENDS in Immunology Vol.28 No.12
Box 1. Putative mechanisms for amyloid plaque clearance via Ab-based immunotherapy Three mechanisms are postulated to account for antibody-mediated amyloid clearance: the first two mechanisms require antibody entrance to the central nervous system. According to the first mechanism, anti-Ab antibodies bind Ab aggregates (fibrils and/or low-molecular weight oligomers) and lead to their dissolution and enhanced clearance [16]. A second mechanism suggests that antiAb antibodies induce Ab clearance via Fc receptor-mediated phagocytosis by activated microglia cells [17,18]. The third mechanism, termed the peripheral sink hypothesis, postulates that Ab antibodies reduce the effective free concentration of Ab in the bloodstream, generating a net efflux of Ab peptides from the brain to the plasma [19].
reduction mediated by anti-b-site antibody was associated with decreased levels of C99, suggesting an inhibition of bsecretase cleavage of APP. The fact that anti-b-site antibodies do not bind Ab or C99 precludes an accelerated degradation of the two as an additional mechanism by which these antibodies mediate their effect. The antibody’s effect on APP degradation has not yet been determined, and thus it is not possible to rule out accelerated degradation of APP as an additional mechanism to the antibody-mediated Ab reduction. Although APP N terminus antibody internalization and trafficking resembled that of anti-b-site antibody, it failed to produce any change in Ab levels, which is similar to the results presented by Tampellini et al. [6]. In another study, monoclonal antibodies 10D5 (Elan Pharmaceuticals) and 196 (produced in our laboratory) directed to the N terminus of Ab, which share an overlapping epitope with 6E10 antibody, failed to bind native human APP expressed on the plasma membrane of CHO cells and thus showed no internalization, probably because of their cryptic epitope (B.S. et al., unpublished data). LaFerla and colleagues investigated the relationship between the extracellular and intracellular Ab pools and suggested a different mechanism from that presented by Tampellini et al. to underline the immunotherapy-mediated intracellular Ab reduction [8]. The authors showed that, in their triple transgenic mice after a single intrahippocampal injection of 6E10 antibody, the extracellular Ab deposits are
Figure 1. Ab antibodies facilitate intraneuronal Ab reduction. A schematic representation of the mechanism postulated by Tampellini et al. [6] for antibodymediated reduction of Ab levels. (a) Ab is generated through the secretory and endocytic pathways. In the endocytic pathway, cell-surface APP and BACE1 molecules are interanalized into the early endosomes, where the acidic conditions favor BACE1 cleavage of APP and the generation of soluble b APP (sAPPb) and C99. A sequential cleavage by g-secretase releases the APP intracellular domain and Ab peptide that tend to aggregate in a concentration-dependent manner. Abcontaining vesicles are either transported to the neuron terminal and then secreted or degraded through the endosomal and lysosomal pathways. (b) Administration of anti-Ab antibodies to the cells results in antibody binding of secreted Ab and cell-surface APP molecules, with the latter being cointernalized to the early endosomes. Antibody binding of cell-surface APP accelerates APP internalization, resulting in decreased levels of cell-surface APP. The increased internalization promotes b-secretase cleavage and thus the production of Ab through the endocytic pathway. (c) Antibody presence within the endocytic vesicles then leads to enhanced degradation of APP cleavage products (Ab and C99) through the endosomal and lysosomal pathways, resulting in decreased intracellular Ab levels. The reduced extracellular Ab levels might derive from either the antibodies’ direct effect on Ab peptides or the decreased intracellular Ab levels, which leads to secretion of a lower concentration of the peptide to the extracellular space. For the purposes of simplicity, Ab production through the secretory pathway and the nonamyloidgenic processing of APP are not represented in this illustration. www.sciencedirect.com
Update
TRENDS in Immunology
cleared first, followed by reduction in the levels of intracellular Ab. The authors further demonstrated that, once the antibody dissipates, intracellular Ab reemerges first, before the appearance of the extracellular Ab pathology. The authors concluded that there is a dynamic relationship between these two pools of Ab. It is possible that these two independent mechanisms suggested by the Gouras and LaFerla groups both contribute to the antibody-mediated clearance of intraneuronal Ab. Accumulating evidence supports the role of intraneuronal Ab accumulation as an early event in AD-associated neuronal dysfunction. In humans, an increase in the level of soluble Ab42, but not in Ab40, was reported in Down syndrome (DS) brains before the appearance of plaques [9]. Postmortem examination of AD brains showed that soluble Ab correlates better with cognitive dysfunction in AD patients rather than extracellular amyloid plaques [10]. Examination of brain tissue from subjects with mild cognitive impairment (MCI) by Gouras and colleagues revealed significant amounts of region-specific intraneuronal immunoreactivity, especially evident within pyramidal neurons of areas such as the hippocampus or entorhinal cortex, which are prone to developing early AD neuropathology. This study also showed that most of the intraneuronal Ab in MCI and AD brains is Ab42, not Ab40 [11]. The same group further demonstrated that Ab42 accumulation in multivesicular bodies of neurons is associated with synaptic dysfunction [12]. Similar results indicating the early emergence of intracellular Ab were also obtained from different AD transgenic mice models (reviewed in [13]). In the triple transgenic mice, impairments in long-term synaptic plasticity correlated with the early accumulation of intraneuronal Ab [14]. Intraneuronal Ab42 accumulation in the 5 FAD mice model (expressing mutated APP- and PS1encoding genes) is evident at a very early age and occurs within neuron soma and neurites before plaque formation [15]. As mentioned above, several lines of evidence support the role of intracellular Ab in the early stages of AD pathogenesis. Understanding the mechanisms that underline Ab accumulation in neurons and its relationship with the extracellular Ab pool might be beneficial in developing therapeutic tools towards treatment of AD. The paper recently published by Gouras and colleagues provides a new insight into the mechanism underlying the beneficial effect of Ab immunotherapy in terms of reduced cerebral Ab and increased cognitive function. However, in the scenario in which Ab antibodies are applied to either AD patients or transgenic mice with preexisting extracellular
Vol.28 No.12
deposits it is more probable that the antibodies will first bind to Ab plaques and lead to their dissolution rather than bind surface APP. This might be an additional and combined mechanism that explains the delayed clearance of intracellular Ab observed by Oddo et al. [8]. References 1 Selkoe, D.J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 2 Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 3 Solomon, B. (2007) Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin. Investig. Drugs 16, 819–828 4 Billings, L.M. et al. (2005) Intraneuronal Ab causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45, 675–688 5 Oddo, S. et al. (2004) Ab immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332 6 Tampellini, D. et al. (2007) Internalized antibodies to the Ab domain of APP reduce neuronal Ab and protect against synaptic alterations. J. Biol. Chem. 282, 18895–18906 7 Arbel, M. et al. (2005) Inhibition of amyloid precursor protein processing by b-secretase through site-directed antibodies. Proc. Natl. Acad. Sci. U. S. A. 102, 7718–7723 8 Oddo, S. et al. (2006) A dynamic relationship between intracellular and extracellular pools of Ab. Am. J. Pathol. 168, 184–194 9 Teller, J.K. et al. (1996) Presence of soluble amyloid b-peptide precedes amyloid plaque formation in Down’s syndrome. Nat. Med. 2, 93–95 10 McLean, C.A. et al. (1999) Soluble pool of Ab amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 46, 860–866 11 Gouras, G.K. et al. (2000) Intraneuronal Ab42 accumulation in human brain. Am. J. Pathol. 156, 15–20 12 Takahashi, R.H. et al. (2002) Intraneuronal Alzheimer Ab42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 161, 1869–1879 13 Laferla, F.M. et al. (2007) Intracellular amyloid-b in Alzheimer’s disease. Nat. Rev. Neurosci. 8, 499–509 14 Oddo, S. et al. (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Ab and synaptic dysfunction. Neuron 39, 409–421 15 Oakley, H. et al. (2006) Intraneuronal b-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 16 Solomon, B. et al. (1997) Disaggregation of Alzheimer b-amyloid by site-directed mAb. Proc. Natl. Acad. Sci. U. S. A. 94, 4109–4112 17 Schenk, D. et al. (1999) Immunization with amyloid-b attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 18 Bard, F. et al. (2000) Peripherally administered antibodies against amyloid b-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 19 DeMattos, R.B. et al. (2001) Peripheral anti-A b antibody alters CNS and plasma A b clearance and decreases brain Ab burden in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 98, 8850– 8855
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TRENDS in Immunology
Vol.28 No.12
Research Focus
Immunotherapy for Alzheimer’s disease: attacking amyloid-b from the inside Michal Arbel and Beka Solomon Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv 69978, Israel
Although extracellular Ab plaques are a hallmark of Alzheimer’s disease, it remains to be determined whether extracellular or intracellular Ab accumulation initiates the disease process. A recent paper from Gunnar Gouras’ group showed that Ab antibodies lead to reduced intracellular Ab levels in neurons via antibody internalization after binding to the Ab domain of amyloid precursor protein (APP) at the plasma membrane. This work suggests novel avenues for the immunotherapy of Alzheimer’s disease. Alzheimer’s disease (AD) is a progressive neurodegeneration and the most common form of dementia in the elderly. The disease is characterized by massive cell loss, especially of cholinergic neurons; deposition of fibrillar amyloid-b (Ab) peptides as senile plaques; and intracellular accumulation of hyperphosphorylated tau protein as neurofibrillary tangles [1]. Although AD pathogenesis is complex and remains unclear, aggregation of Ab peptides is considered to be the first known event in a complex cascade eventually leading to neurodegeneration [2]. Emerging evidences that will be discussed below suggest a pivotal role for intracellular Ab accumulation in the early stages of AD pathogenesis. Antibodies against Ab peptides are effective in reducing Ab levels and plaque pathology, as well as attenuating cognitive deficits in AD animal models (reviewed in [3]). Passive and active Ab immunizations of the AD triple transgenic mice model (3 Tg), which overexpress mutated amyloid precursor protein (APP)-, Presenilin 1 (PS1)-, and tau-encoding genes, led to reduction of both extracellular and intracellular Ab levels, with the latter correlated with cognitive improvement [4,5]. Despite the fact that the extracellular Ab plaques are a hallmark of AD and are considered criteria for an ultimate postmortem diagnosis of the disease, it is yet to be determined whether extracellular Ab deposition or intracellular Ab accumulation initiates the disease process. Three distinct mechanisms (discussed in Box 1) have been suggested for antibody-mediated clearance of the extracellular Ab deposits. Unlike the mechanisms suggested for the extracellular Ab reduction, the mechanism by which anti-Ab antibodies affect intracellular Ab is unclear. A recent paper by Gouras and colleagues offered an interesting, novel mechanism by which Corresponding author: Solomon, B. ([email protected]). Available online 5 November 2007. www.sciencedirect.com
anti-Ab antibodies mediate intraneuronal Ab reduction [6]. To investigate the mechanism by which anti-Ab antibodies mediate the intracellular Ab reduction, Tampellini et al. [6] performed an extensive work and employed both a neuronal cell line and primary neurons extracted from the Tg2576 AD transgenic mice model. This work provides evidence that anti-Ab antibodies reduce intracellular Ab levels in cultured neurons and protect against synaptic dysfunction. Utilizing 6E10 and 4G8 antibodies, which are directed to the N terminus and mid-region of Ab, respectively, the authors showed that the antibodies are internalized into the cells by binding to the Ab sequence of the APP molecule. Antibody internalization via endocytosis is required, yet alone insufficient, for intracellular Ab reduction, as evidenced by APP N terminus antibody, which internalizes into the cells in a similar manner to Ab antibodies, but did not alter Ab levels. These results suggest that antibody-mediated reduction in Ab levels relies on its binding to the Ab sequence of APP. Importantly, Ab C-terminal specific antibody, which does not bind APP, failed to enter the cells and affect intracellular Ab levels. The authors excluded an increase in Ab secretion and decreased processing of APP by both band g-secretase as possible mechanisms for Ab clearance. Interestingly, the related products of b-secretase cleavage C99 and soluble bAPP were elevated, suggesting that antibody internalization after APP binding in fact promotes b-secretase cleavage. Finally, the authors further propose a scenario in which anti-Ab antibodies accelerate APP internalization into the early endosomes, where increased BACE1 (b-secretase) cleavage occurs, followed by an enhanced degradation of the cleavage products (Ab and C99) through the endosomal and lysosomal pathways. These steps are illustrated in Figure 1. The results in this study support our previously reported data regarding antibody directed to the b-secretase cleavage site of the APP molecule (b-site) in spite of the fact that this antibody does not bind any form of Ab [7]. Anti-b-site antibody was shown to internalize into the cell after APP binding at the plasma membrane and to significantly reduce intracellular Ab levels. The trafficking of anti-b-site antibody is similar to that reported for Ab antibodies by the Gouras group; anti-b-site antibody is colocalized with an early endosome marker starting at 2 min after incubation and is evident at the lysosomes at later time points (from 45 min and later; unpublished data). Inconsistent with their results, intracellular Ab
1471-4906/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2007.09.005
512
Update
TRENDS in Immunology Vol.28 No.12
Box 1. Putative mechanisms for amyloid plaque clearance via Ab-based immunotherapy Three mechanisms are postulated to account for antibody-mediated amyloid clearance: the first two mechanisms require antibody entrance to the central nervous system. According to the first mechanism, anti-Ab antibodies bind Ab aggregates (fibrils and/or low-molecular weight oligomers) and lead to their dissolution and enhanced clearance [16]. A second mechanism suggests that antiAb antibodies induce Ab clearance via Fc receptor-mediated phagocytosis by activated microglia cells [17,18]. The third mechanism, termed the peripheral sink hypothesis, postulates that Ab antibodies reduce the effective free concentration of Ab in the bloodstream, generating a net efflux of Ab peptides from the brain to the plasma [19].
reduction mediated by anti-b-site antibody was associated with decreased levels of C99, suggesting an inhibition of bsecretase cleavage of APP. The fact that anti-b-site antibodies do not bind Ab or C99 precludes an accelerated degradation of the two as an additional mechanism by which these antibodies mediate their effect. The antibody’s effect on APP degradation has not yet been determined, and thus it is not possible to rule out accelerated degradation of APP as an additional mechanism to the antibody-mediated Ab reduction. Although APP N terminus antibody internalization and trafficking resembled that of anti-b-site antibody, it failed to produce any change in Ab levels, which is similar to the results presented by Tampellini et al. [6]. In another study, monoclonal antibodies 10D5 (Elan Pharmaceuticals) and 196 (produced in our laboratory) directed to the N terminus of Ab, which share an overlapping epitope with 6E10 antibody, failed to bind native human APP expressed on the plasma membrane of CHO cells and thus showed no internalization, probably because of their cryptic epitope (B.S. et al., unpublished data). LaFerla and colleagues investigated the relationship between the extracellular and intracellular Ab pools and suggested a different mechanism from that presented by Tampellini et al. to underline the immunotherapy-mediated intracellular Ab reduction [8]. The authors showed that, in their triple transgenic mice after a single intrahippocampal injection of 6E10 antibody, the extracellular Ab deposits are
Figure 1. Ab antibodies facilitate intraneuronal Ab reduction. A schematic representation of the mechanism postulated by Tampellini et al. [6] for antibodymediated reduction of Ab levels. (a) Ab is generated through the secretory and endocytic pathways. In the endocytic pathway, cell-surface APP and BACE1 molecules are interanalized into the early endosomes, where the acidic conditions favor BACE1 cleavage of APP and the generation of soluble b APP (sAPPb) and C99. A sequential cleavage by g-secretase releases the APP intracellular domain and Ab peptide that tend to aggregate in a concentration-dependent manner. Abcontaining vesicles are either transported to the neuron terminal and then secreted or degraded through the endosomal and lysosomal pathways. (b) Administration of anti-Ab antibodies to the cells results in antibody binding of secreted Ab and cell-surface APP molecules, with the latter being cointernalized to the early endosomes. Antibody binding of cell-surface APP accelerates APP internalization, resulting in decreased levels of cell-surface APP. The increased internalization promotes b-secretase cleavage and thus the production of Ab through the endocytic pathway. (c) Antibody presence within the endocytic vesicles then leads to enhanced degradation of APP cleavage products (Ab and C99) through the endosomal and lysosomal pathways, resulting in decreased intracellular Ab levels. The reduced extracellular Ab levels might derive from either the antibodies’ direct effect on Ab peptides or the decreased intracellular Ab levels, which leads to secretion of a lower concentration of the peptide to the extracellular space. For the purposes of simplicity, Ab production through the secretory pathway and the nonamyloidgenic processing of APP are not represented in this illustration. www.sciencedirect.com
Update
TRENDS in Immunology
cleared first, followed by reduction in the levels of intracellular Ab. The authors further demonstrated that, once the antibody dissipates, intracellular Ab reemerges first, before the appearance of the extracellular Ab pathology. The authors concluded that there is a dynamic relationship between these two pools of Ab. It is possible that these two independent mechanisms suggested by the Gouras and LaFerla groups both contribute to the antibody-mediated clearance of intraneuronal Ab. Accumulating evidence supports the role of intraneuronal Ab accumulation as an early event in AD-associated neuronal dysfunction. In humans, an increase in the level of soluble Ab42, but not in Ab40, was reported in Down syndrome (DS) brains before the appearance of plaques [9]. Postmortem examination of AD brains showed that soluble Ab correlates better with cognitive dysfunction in AD patients rather than extracellular amyloid plaques [10]. Examination of brain tissue from subjects with mild cognitive impairment (MCI) by Gouras and colleagues revealed significant amounts of region-specific intraneuronal immunoreactivity, especially evident within pyramidal neurons of areas such as the hippocampus or entorhinal cortex, which are prone to developing early AD neuropathology. This study also showed that most of the intraneuronal Ab in MCI and AD brains is Ab42, not Ab40 [11]. The same group further demonstrated that Ab42 accumulation in multivesicular bodies of neurons is associated with synaptic dysfunction [12]. Similar results indicating the early emergence of intracellular Ab were also obtained from different AD transgenic mice models (reviewed in [13]). In the triple transgenic mice, impairments in long-term synaptic plasticity correlated with the early accumulation of intraneuronal Ab [14]. Intraneuronal Ab42 accumulation in the 5 FAD mice model (expressing mutated APP- and PS1encoding genes) is evident at a very early age and occurs within neuron soma and neurites before plaque formation [15]. As mentioned above, several lines of evidence support the role of intracellular Ab in the early stages of AD pathogenesis. Understanding the mechanisms that underline Ab accumulation in neurons and its relationship with the extracellular Ab pool might be beneficial in developing therapeutic tools towards treatment of AD. The paper recently published by Gouras and colleagues provides a new insight into the mechanism underlying the beneficial effect of Ab immunotherapy in terms of reduced cerebral Ab and increased cognitive function. However, in the scenario in which Ab antibodies are applied to either AD patients or transgenic mice with preexisting extracellular
Vol.28 No.12
deposits it is more probable that the antibodies will first bind to Ab plaques and lead to their dissolution rather than bind surface APP. This might be an additional and combined mechanism that explains the delayed clearance of intracellular Ab observed by Oddo et al. [8]. References 1 Selkoe, D.J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 2 Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 3 Solomon, B. (2007) Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin. Investig. Drugs 16, 819–828 4 Billings, L.M. et al. (2005) Intraneuronal Ab causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45, 675–688 5 Oddo, S. et al. (2004) Ab immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332 6 Tampellini, D. et al. (2007) Internalized antibodies to the Ab domain of APP reduce neuronal Ab and protect against synaptic alterations. J. Biol. Chem. 282, 18895–18906 7 Arbel, M. et al. (2005) Inhibition of amyloid precursor protein processing by b-secretase through site-directed antibodies. Proc. Natl. Acad. Sci. U. S. A. 102, 7718–7723 8 Oddo, S. et al. (2006) A dynamic relationship between intracellular and extracellular pools of Ab. Am. J. Pathol. 168, 184–194 9 Teller, J.K. et al. (1996) Presence of soluble amyloid b-peptide precedes amyloid plaque formation in Down’s syndrome. Nat. Med. 2, 93–95 10 McLean, C.A. et al. (1999) Soluble pool of Ab amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 46, 860–866 11 Gouras, G.K. et al. (2000) Intraneuronal Ab42 accumulation in human brain. Am. J. Pathol. 156, 15–20 12 Takahashi, R.H. et al. (2002) Intraneuronal Alzheimer Ab42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 161, 1869–1879 13 Laferla, F.M. et al. (2007) Intracellular amyloid-b in Alzheimer’s disease. Nat. Rev. Neurosci. 8, 499–509 14 Oddo, S. et al. (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Ab and synaptic dysfunction. Neuron 39, 409–421 15 Oakley, H. et al. (2006) Intraneuronal b-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 16 Solomon, B. et al. (1997) Disaggregation of Alzheimer b-amyloid by site-directed mAb. Proc. Natl. Acad. Sci. U. S. A. 94, 4109–4112 17 Schenk, D. et al. (1999) Immunization with amyloid-b attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 18 Bard, F. et al. (2000) Peripherally administered antibodies against amyloid b-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 19 DeMattos, R.B. et al. (2001) Peripheral anti-A b antibody alters CNS and plasma A b clearance and decreases brain Ab burden in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 98, 8850– 8855
Reproduction of material from Elsevier articles Interested in reproducing part or all of an article published by Elsevier, or one of our article figures? If so, please contact our Global Rights Department with details of how and where the requested material will be used. To submit a permission request online, please visit:
www.elsevier.com/locate/permissions www.sciencedirect.com
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