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Amyloid, memory and neurogenesis
Experimental Neurology 205 (2007) 330 – 335 www.elsevier.com/locate/yexnr
Commentary
Amyloid, memory and neurogenesis Dave Morgan ⁎ Alzheimer Research Laboratory, Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, College of Medicine, 12901 BB Downs Blvd. MDC Box 9, University of South Florida, Tampa, FL 33612, USA Received 9 January 2007; revised 22 February 2007; accepted 6 March 2007 Available online 14 March 2007
Abstract Transgenic mouse models of amyloid deposition consistently demonstrate impaired performance on certain tasks of learning and memory. The article by Zhang et al. (2006) demonstrates reductions in dentate gyrus neurogenesis in a murine model of amyloid deposition which is linked to the deposition of amyloid and not overexpression of transgenes. Neurogenesis plays at least a facilitatory role in the formation of memory, the nature of which is only beginning to emerge. Thus, it seems reasonable to propose that the memory deficits found in the amyloid precursor protein transgenic mouse models of amyloid deposition result, at least in part, from reduced rates of hippocampal neurogenesis. The possible relationship to memory loss in Alzheimer's dementia is also discussed. © 2007 Published by Elsevier Inc.
The Zhang et al. (2006) paper uses a very important mouse model of amyloid deposition, which is based exclusively on gene replacement rather than transgenesis. As a result, these mice have several advantages over amyloid precursor protein (APP) transgenic mice that are produced by pronuclear injection. First, success in producing APP transgenic mice which deposit amyloid is a rare event (see Greenberg et al., 1996, for a discussion of the multiple failures during the early 1990s). Second, the successful APP mice have multiple copies of the transgene in addition to the endogenous murine APP genes, leading to considerable APP overexpression (3-fold minimum). The impact of excess APP has been a potential confound in virtually all examinations of the APP transgenic mouse phenotype. Third, the APP expression is driven by a heterologous promoter, leading to inappropriate regulation of APP expression limited largely to neurons, which may not be the major site of APP expression in all conditions (Wright et al., 1999). For example, the “inflammation hypothesis” of Alzheimer pathogenesis posits a vicious cycle of Aβ, inflammation and elevated APP, leading to more Aβ. In most APP mouse
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models, provocation of inflammatory conditions clears amyloid instead of provoking pathogenesis (Morgan et al., 2005; WyssCoray, 2006). The promoter driving the APP transgenic in mice likely does not respond to inflammatory conditions the same as the APP promoter, leading to concerns the inflammation hypothesis may not be reliably tested in these mice. The homozygous knock-in human APP (K670N;M671L) mice crossed with the homozygous knock-in human presenilin-1 (P264L) has none of these confounds. Thus interpretation of results can be made without the caveat that APP overexpression may also contribute to the phenotype. Indeed, it was not certain that the Aβ produced in association with the APP overexpression in transgenic models was the cause of memory deficits in these mice until the APP mice were bred onto a BACE1 null background, eliminating Aβ production while preserving APP overexpression (Ohno et al., 2004). Thus the results obtained in this knock-in mouse model of amyloid deposition can be confidently attributed to Aβ overproduction rather than excessive or inappropriate transgene expression. The data show quite convincingly that the numbers of immature neuronal cells labeled by doublecortin (less than 3 weeks old; Christie and Cameron, 2006) are dramatically reduced in the APP/PS1 mice that deposit amyloid. This is not observed in mice with only the APP gene knocked-in or the PS1 gene knocked-in.
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Moreover, the subventricular zone/olfactory bulb neurogenesis pathway (the rostral migratory stream), a region lacking amyloid deposition, is unaffected. Thus, in the absence of APP overexpression, these data argue strongly that excess Aβ production can reduce the abundance of recently born neurons in the dentate gyrus. Secondarily the authors provide evidence that the numbers of both stem and progenitor cells are similarly reduced in these animals. This would argue that the effects of Aβ are not on rates of cell proliferation, but the development and/or maintenance of the neuronal progenitor populations.
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pool of these neurons will remain for some period of time after irradiation. Only when the pool of uncommitted neurons is exhausted by either high task complexity, time or multiple behavioral tests would the deficits become apparent. There may be some analogy to immune system memory, where a broad spectrum of naive B cells are needed for development of effective immunity (by formation of memory cells). At the moment, this proposition remains speculative, but is consistent with the limited data available. Amyloid, Memory and Neurogenesis
Neurogenesis and Memory The role of hippocampal neurogenesis in learning and memory is complex, but clearly is related to events involved with the acquisition of new information. There are multiple manipulations that impact neurogenesis which also modify learning and memory. It is conceivable that manipulations may (a) modify mitotic activity of progenitor cells, (b) modify the differentiation and survival of these new cells into neurons, or both. Unfortunately, not all studies have consistently evaluated these actions independently, and most have examined the numbers of recently born neurons at 1 or more weeks after the manipulation. One of the more striking observations was that environmental enrichment, a manipulation known for 40 years to enhance learning and memory function in rodents, also increased hippocampal neurogenesis (Kempermann et al., 1997). Not only were more neurons being produced, but the neuronal complement was increased in the granule cell layer of the dentate gyrus by 15%. Conversely, aged rodents, known to have deficits in learning and memory functions, exhibit dramatic reduction in hippocampal neurogenesis (Kuhn et al., 1996). In addition, both physical exercise and administration of learning tasks can increase rates of neurogenesis (van Praag et al., 1999; Gould et al., 1999). Finally, production of inflammation in the central nervous system can produce both learning and memory deficits and reductions in neurogenesis, both of which can be attenuated by nonsteroidal anti-inflammatory agents (HaussWegrzyniak et al., 1999; Monje et al., 2003; Ekdahl et al., 2003). Thus, there are good correlations between neurogenesis and learning and memory in a number of conditions. A more vexing issue has concerned the role of new neurons in the formation of memories. Shors et al. (2001) found that inhibiting the formation of new neurons with an antimitotic chemical caused impairment in trace eyeblink conditioning (a hippocampus dependent task) but not delay eyeblink conditioning (a hippocampus independent task). An alternative to antimitotic agents is to focally irradiate the adult hippocampus, causing a dramatic and long lasting reduction in hippocampal neurogenesis. This manipulation also impairs hippocampusdependent learning and memory performance, while not impacting tasks less dependent on hippocampal activity (Madsen et al., 2003; Rola et al., 2004; Raber et al., 2004). However, not all hippocampal tasks are impacted by focal irradiation (see discussion by Leuner et al., 2006). This author feels part of the problem may be that recently born, naive, uncommitted neurons are needed for learning new tasks, and that a slowly diminishing
The role of accumulations of the Aβ peptide in causing memory disturbance of APP mice has received considerable attention in the past decade. Very early in their study, APP transgenic mice were found to have cognitive deficits (Hsiao et al., 1996; Holcomb et al., 1998), and the degree of mnemonic impairment was correlated with the extent of Aβ accumulation in individual animals (Dodart et al., 1999; Chen et al., 2000; Gordon et al., 2001). Our group was the first to show that reducing the amyloid deposition (in this case with vaccination) also reduced the behavioral phenotype in the APP transgenic mice (Morgan et al., 2000). While this was a comforting outcome, the association between amyloid plaques and memory disruption was challenged by observations of memory dysfunction in mice that never developed amyloid plaque pathology (Moran et al., 1995; Hsia et al., 1999; Koistinaho et al., 2001). In other circumstances, early testing of some mouse strains revealed some forms of memory disruption prior to the appearance of amyloid deposits (Holcomb et al., 1999; Westerman et al., 2002; Richardson et al., 2003; Lee et al., 2004). Importantly, the deterioration of memory function as mice aged was not linearly related to the increasing amount of Aâ in the brain (Westerman et al., 2002; Trinchese et al., 2004). One potential explanation for this nonlinear relationship between Aβ deposition and memory disruption is the presence of toxic intermediate stages of Aβ aggregates that are neither monomer, nor fully fibrillar forms. These are referred to as oligomers of Aβ or ADDLs (Walsh et al., 2002; Kayed et al., 2003; Klein et al., 2004). Recent data suggest that these intermediate sized Aβ aggregates are the best correlates of memory disturbance in the APP transgenic mouse models of amyloid deposition (Lesne et al., 2006). Nonetheless, many questions remain regarding these aggregates. Typically these aggregates are generated either in vitro or in cell culture systems. Do the same types of aggregates formed in vitro or in culture also exist in vivo? Are all the different reported intermediate aggregates actually the same, or are there important differences dependent upon how they were generated? Certainly the clarification of these issues and the definition of the in vivo role of oligomers in both the APP models of amyloid deposition and in Alzheimer patients are exciting areas of endeavor. These may be the molecular form most closely linked to the suppression of neurogenesis reported byZhang et al. (2006). The results observed by Zhang et al. with respect to neurogenesis are part of a growing list of papers showing that amyloid deposition is linked to reduced formation of new
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neurons from neural precursors born during adulthood in the subgranular layer of the dentate gyrus. Haughey et al. (2002) found reduced proliferation and differentiation of neurons in APPsw mice developed by Borchelt et al. (1997). Dong et al. (2004) also found reduced proliferation of dentate neurons in Tg2576 APP transgenic mice. Donovan et al. (2006) using PDAPP mice found reduced proliferation and survival of new neurons in the subgranular zone, but not in the outer molecular layer of the dentate (a numerically minor component of the proliferating cells). Rockenstein et al. (2007) recently reported decreased neural differentiation in mThy1-hAPP751 mice. Consistent with a role of Aβ deposits in regulating neurogenesis are reports demonstrating that removal of amyloid deposits using either immunization (Becker et al., 2007) or cerebrolysin treatment (Rockenstein et al., 2007) leads to increased neurogenesis in dentate gyrus, implying that amyloid is responsible for the reduced census of newly born neurons. The only exception to this observation of general decline of neurogenesis in amyloid depositing mice was Jin et al. (2004) using an APPsw line developed by Hsia et al. (1999). They reported increased numbers of cells at 7 days after bromodeoxyuridine injection, but did not examine longer times after the injection, which would be needed to observe differentiation and survival into neurons. Studies of mice with genetic modifications of presenilin-1, have led to mixed outcomes, but in no case did these mice deposit amyloid (Feng et al., 2001; Wen et al., 2002, 2004). Thus, in the APP transgenic mouse models, the data are largely consistent with the argument that amyloid reduces neurogenesis. Recently a series of papers have addressed the question of environmental enrichment in APP transgenic mouse models. Although the studies are not in total agreement, environmental enrichment does appear to reduce amyloid loads (Lazarov et al., 2005; Costa et al., 2006; Ambree et al., 2006) and to improve cognitive performance (Jankowsky et al., 2005; Costa et al., 2006). Most recently Wolf et al. (2006) contrasted the effects of environmental enrichment with simple increases in physical activity on neurogenesis in the APP-23 mouse model of amyloid deposition. They found that enrichment increases neurogenesis and protects from memory impairments in APP mice. However, physical activity alone achieves neither increased neurogenesis nor protection from memory impairment. Coupled with the results showing that Aβ reduces neurogenesis in APP mice from Zhang et al. (2006), these data link this reduction in neurogenesis to the cognitive impairments in amyloid depositing mice. Memory Deficits in Alzheimer's Disease A broader question is with regard to linkage of changes in the murine models to Alzheimer's disease. In general, the most striking feature of the multiple well characterized APP transgenic mouse models is how similar they are. All show a progressive accumulation of Aβ deposits over the lifespan and these appear first and most intensely in the hippocampus and dorsal and anterior cortices (Games et al., 1995; Hsiao et al., 1996; Borchelt et al., 1997; Sturchler-Pierrat et al., 1997;
Holcomb et al., 1998; Janus et al., 2000). These deposits include both diffuse deposits and compacted plaques stained by Congo red, Thioflavin S and surrounded by dystrophic neurites (Gordon et al., 2002). All develop glial reactions surrounding the compacted deposits and have elevated levels of markers for inflammation (Morgan et al., 2005). These features of amyloid deposition are virtually identical to those found in Alzheimer tissue postmortem, and generally the same in all the mice irrespective of the APP mutation or the promoter used to drive expression of the transgene. Even the histological distribution of Aβ40 and Aβ42 is similar to that found in the Alzheimer tissue, with Aβ40 in vascular deposits and compacted deposits and Aβ42 in diffuse deposits and compacted deposits (Gordon et al., 2002). Thus, they are excellent reproductions of amyloid deposition in Alzheimer brain, and are valid systems in which to address scientific questions relating to that process. In general, the differences between the different models are unlikely to interfere with generalizing from one such model to another. Nonetheless, there are important features of Alzheimer's disease which are absent in these models. With the exception of the triple transgenic model (Oddo et al., 2003), none of the models have both amyloid deposits and fibrillar aggregations of hyperphosphorylated tau (neurofibrillary tangles). Perhaps most importantly, there is no widespread neuron loss in hippocampus or cortex (Irizarry et al., 1997; Calhoun et al., 1998; Takeuchi et al., 2000). This contrasts with the degeneration found in the Alzheimer brain which is so profound that it ultimately causes the death of the individual. Beyond memory and cognitive functions, even basic neural functions are lost such as bowel and bladder control and reflexes such as coughing, leading patients drown in their pulmonary secretions. The question that arises is whether the learning and memory impairments that develop in these mice are analogous to those found in Alzheimer patients. While the linkage to at least some form of amyloid production is very strong for the murine impairments, it is unclear if this has a counterpart in the Alzheimer brain. One difference is that the transgenic mice do not progress to the profound neural dysfunction found in Alzheimer patients. While there is accelerated mortality early in life of APP transgenics (Carlson et al., 1997) we find that this excess attrition abates by 12 months when amyloid deposits are building up. We find that after APP mice reach mid life, their survival rivals that of nontransgenic littermates, with mice easily reaching 28 months (Wilcock et al., 2004). Thus the cognitive disturbance in the APP mice is not as progressive or life threatening as in Alzheimer's. Some have speculated that the memory loss in these mice probably resembles that of very early stage Alzheimer patients or, perhaps, individuals with mild cognitive impairment. However, even for individuals in these incipient stages, postmortem analysis finds considerable neuron and synapse loss (Morris and Price, 2001), most probably accounting for the cognitive changes. A final concern about a role for amyloid per se in causing the cognitive deterioration in Alzheimer cases is the so-called high plaque normals; cases that come to autopsy with a full load of amyloid, but have no symptoms of dementia
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(Crystal et al., 1988; Davis et al., 1999; Knopman et al., 2003). Intriguingly, one report claims that these high plaque normal cases differ from Alzheimer cases in that they lack the inflammatory reactions (Lue et al., 1996). Given the observation that some inflammatory processes are present in the mice studied by Zhang et al. (2006), this may be the common factor associated with cognitive disruption. In conclusion, hippocampal neurogenesis appears to have some role in memory formation, but the exact nature of that role is not yet clear. Memory loss in mouse models of amyloid deposition is quite consistent, but its relevance to the cognitive deterioration found in Alzheimer patients is also unclear. Nonetheless, the strong evidence that amyloid can suppress neurogenesis, and that other manipulations that impact neurogenesis can also modify memory in APP transgenic mice, strongly points to this as an intriguing link in the steps leading from amyloid formation to memory disruption in transgenic mice, and possibly in Alzheimer patients. Acknowledgments D.M. is supported by the following awards from NIH: AG04418, AG15490, AG 18478, AG25509, AG 25711 and NS 48335. References Ambree, O., Leimer, U., Herring, A., Gortz, N., Sachser, N., Heneka, M.T., Paulus, W., Keyvani, K., 2006. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am. J. Pathol. 169, 544–552. Becker, M., Lavie, V., Solomon, B., 2007. Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 104, 1691–1696. Borchelt, D.R., Ratovitski, T., Van Lare, J., Lee, M.K., Gonzales, V., Jenkins, N.A., Copeland, N.G., Price, D.L., Sisodia, S.S., 1997. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor protein. Neuron 19, 939–945. Calhoun, M.E., Wiederhold, K.H., Abramowski, D., Phinney, A.L., Probst, A., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., Jucker, M., 1998. Neuron loss in APP transgenic mice [letter]. Nature 395, 755–756. Carlson, G.A., Borchelt, D.R., Dake, A., Turner, S., Danielson, V., Coffin, J.D., Eckman, C., Meiners, J., Nilsen, S., Younkin, S.G., Hsiao, K., 1997. Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum. Mol. Genet. 6 (11), 1951–1959. Chen, G., Chen, K.S., Knox, J., Inglis, J., Bernard, A., Martin, S.J., Justice, A., McConlogue, L., Games, D., Freedman, S.B., Morris, R.G., 2000. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408, 975–979. Christie, B.R., Cameron, H.A., 2006. Neurogenesis in the adult hippocampus. Hippocampus 16, 199–207. Costa, D.A., Cracchiolo, J.R., Bachstetter, A.D., Hughes, T.F., Bales, K.R., Paul, S.M., Mervis, R.F., Arendash, G.W., Potter, H., 2006. Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms. Neurobiol. Aging. Crystal, H., Dickson, D., Fuld, P., Masur, D., Scott, R., Mehler, M., Masdeu, J., Kawas, C., Aronson, M., Wolfson, L., 1988. Clinico-pathological studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 38, 1682–1687. Davis, D.G., Schmitt, F.A., Wekstein, D.R., Markesbery, W.R., 1999. Alzheimer neuropathologic alterations in aged cognitively normal subjects. J. Neuropathol. Exp. Neurol. 58, 376–388.
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mild cognitive impairment, and early-stage Alzheimer's disease. J. Mol. Neurosci. 17, 101–118. Oddo, S., Caccamo, A., Shepherd, J.D., Murphy, M.P., Golde, T.E., Kayed, R., Metherate, R., Mattson, M.P., Akbari, Y., LaFerla, F.M., 2003. Tripletransgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421. Ohno, M., Sametsky, E.A., Younkin, L.H., Oakley, H., Younkin, S.G., Citron, M., Vassar, R., Disterhoft, J.F., 2004. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41, 27–33. Raber, J., Rola, R., LeFevour, A., Morhardt, D., Curley, J., Mizumatsu, S., VandenBerg, S.R., Fike, J.R., 2004. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat. Res. 162, 39–47. Richardson, J.C., Kendal, C.E., Anderson, R., Priest, F., Gower, E., Soden, P., Gray, R., Topps, S., Howlett, D.R., Lavender, D., Clarke, N.J., Barnes, J.C., Haworth, R., Stewart, M.G., Rupniak, H.T., 2003. Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer's disease. Neuroscience 122, 213–228. Rockenstein, E., Mante, M., Adame, A., Crews, L., Moessler, H., Masliah, E., 2007. Effects of cerebrolysintrade mark on neurogenesis in an APP transgenic model of Alzheimer's disease. Acta Neuropathol. (Berl). 113, 265–275. Rola, R., Raber, J., Rizk, A., Otsuka, S., VandenBerg, S.R., Morhardt, D.R., Fike, J.R., 2004. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp. Neurol. 188, 316–330. Shors, T.J., Miesegaes, G., Beylin, A., Zhao, M., Rydel, T., Gould, E., 2001. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372–376. Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.H., Mistl, C., Rothacher, S., Ledermann, B., Burki, K., Frey, P., Paganetti, P.A., Waridel, C., Calhoun, M.E., Jucker, M., Probst, A., Staufenbiel, M., Sommer, B., 1997. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. U. S. A. 94, 13287–13292. Takeuchi, A., Irizarry, M.C., Duff, K., Saido, T.C., Hsiao, A.K., Hasegawa, M., Mann, D.M., Hyman, B.T., Iwatsubo, T., 2000. Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am. J. Pathol. 157, 331–339. Trinchese, F., Liu, S., Battaglia, F., Walter, S., Mathews, P.M., Arancio, O., 2004. Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann. Neurol. 55, 801–814. van Praag, H., Christie, B.R., Sejnowski, T.J., Gage, F.H., 1999. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. U. S. A. 96, 13427–13431. Walsh, D.M., Klyubin, I., Fadeeva, J.V., Cullen, W.K., Anwyl, R., Wolfe, M.S., Rowan, M.J., Selkoe, D.J., 2002. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539. Wen, P.H., Shao, X., Shao, Z., Hof, P.R., Wisniewski, T., Kelley, K., Friedrich Jr., V.L., Ho, L., Pasinetti, G.M., Shioi, J., Robakis, N.K., Elder, G.A., 2002. Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol. Dis. 10, 8–19. Wen, P.H., Hof, P.R., Chen, X., Gluck, K., Austin, G., Younkin, S.G., Younkin, L.H., DeGasperi, R., Gama Sosa, M.A., Robakis, N.K., Haroutunian, V., Elder, G.A., 2004. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp. Neurol. 188, 224–237. Westerman, M.A., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L.H., Carlson, G.A., Younkin, S.G., Ashe, K.H., 2002. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J. Neurosci. 22, 1858–1867. Wilcock, D.M., Rojiani, A., Rosenthal, A., Levkowitz, G., Subbarao, S., Alamed, J., Wilson, D., Wilson, N., Freeman, M.J., Gordon, M.N., Morgan, D., 2004. Passive amyloid immunotherapy clears amyloid and transiently
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Commentary
Amyloid, memory and neurogenesis Dave Morgan ⁎ Alzheimer Research Laboratory, Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, College of Medicine, 12901 BB Downs Blvd. MDC Box 9, University of South Florida, Tampa, FL 33612, USA Received 9 January 2007; revised 22 February 2007; accepted 6 March 2007 Available online 14 March 2007
Abstract Transgenic mouse models of amyloid deposition consistently demonstrate impaired performance on certain tasks of learning and memory. The article by Zhang et al. (2006) demonstrates reductions in dentate gyrus neurogenesis in a murine model of amyloid deposition which is linked to the deposition of amyloid and not overexpression of transgenes. Neurogenesis plays at least a facilitatory role in the formation of memory, the nature of which is only beginning to emerge. Thus, it seems reasonable to propose that the memory deficits found in the amyloid precursor protein transgenic mouse models of amyloid deposition result, at least in part, from reduced rates of hippocampal neurogenesis. The possible relationship to memory loss in Alzheimer's dementia is also discussed. © 2007 Published by Elsevier Inc.
The Zhang et al. (2006) paper uses a very important mouse model of amyloid deposition, which is based exclusively on gene replacement rather than transgenesis. As a result, these mice have several advantages over amyloid precursor protein (APP) transgenic mice that are produced by pronuclear injection. First, success in producing APP transgenic mice which deposit amyloid is a rare event (see Greenberg et al., 1996, for a discussion of the multiple failures during the early 1990s). Second, the successful APP mice have multiple copies of the transgene in addition to the endogenous murine APP genes, leading to considerable APP overexpression (3-fold minimum). The impact of excess APP has been a potential confound in virtually all examinations of the APP transgenic mouse phenotype. Third, the APP expression is driven by a heterologous promoter, leading to inappropriate regulation of APP expression limited largely to neurons, which may not be the major site of APP expression in all conditions (Wright et al., 1999). For example, the “inflammation hypothesis” of Alzheimer pathogenesis posits a vicious cycle of Aβ, inflammation and elevated APP, leading to more Aβ. In most APP mouse
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models, provocation of inflammatory conditions clears amyloid instead of provoking pathogenesis (Morgan et al., 2005; WyssCoray, 2006). The promoter driving the APP transgenic in mice likely does not respond to inflammatory conditions the same as the APP promoter, leading to concerns the inflammation hypothesis may not be reliably tested in these mice. The homozygous knock-in human APP (K670N;M671L) mice crossed with the homozygous knock-in human presenilin-1 (P264L) has none of these confounds. Thus interpretation of results can be made without the caveat that APP overexpression may also contribute to the phenotype. Indeed, it was not certain that the Aβ produced in association with the APP overexpression in transgenic models was the cause of memory deficits in these mice until the APP mice were bred onto a BACE1 null background, eliminating Aβ production while preserving APP overexpression (Ohno et al., 2004). Thus the results obtained in this knock-in mouse model of amyloid deposition can be confidently attributed to Aβ overproduction rather than excessive or inappropriate transgene expression. The data show quite convincingly that the numbers of immature neuronal cells labeled by doublecortin (less than 3 weeks old; Christie and Cameron, 2006) are dramatically reduced in the APP/PS1 mice that deposit amyloid. This is not observed in mice with only the APP gene knocked-in or the PS1 gene knocked-in.
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Moreover, the subventricular zone/olfactory bulb neurogenesis pathway (the rostral migratory stream), a region lacking amyloid deposition, is unaffected. Thus, in the absence of APP overexpression, these data argue strongly that excess Aβ production can reduce the abundance of recently born neurons in the dentate gyrus. Secondarily the authors provide evidence that the numbers of both stem and progenitor cells are similarly reduced in these animals. This would argue that the effects of Aβ are not on rates of cell proliferation, but the development and/or maintenance of the neuronal progenitor populations.
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pool of these neurons will remain for some period of time after irradiation. Only when the pool of uncommitted neurons is exhausted by either high task complexity, time or multiple behavioral tests would the deficits become apparent. There may be some analogy to immune system memory, where a broad spectrum of naive B cells are needed for development of effective immunity (by formation of memory cells). At the moment, this proposition remains speculative, but is consistent with the limited data available. Amyloid, Memory and Neurogenesis
Neurogenesis and Memory The role of hippocampal neurogenesis in learning and memory is complex, but clearly is related to events involved with the acquisition of new information. There are multiple manipulations that impact neurogenesis which also modify learning and memory. It is conceivable that manipulations may (a) modify mitotic activity of progenitor cells, (b) modify the differentiation and survival of these new cells into neurons, or both. Unfortunately, not all studies have consistently evaluated these actions independently, and most have examined the numbers of recently born neurons at 1 or more weeks after the manipulation. One of the more striking observations was that environmental enrichment, a manipulation known for 40 years to enhance learning and memory function in rodents, also increased hippocampal neurogenesis (Kempermann et al., 1997). Not only were more neurons being produced, but the neuronal complement was increased in the granule cell layer of the dentate gyrus by 15%. Conversely, aged rodents, known to have deficits in learning and memory functions, exhibit dramatic reduction in hippocampal neurogenesis (Kuhn et al., 1996). In addition, both physical exercise and administration of learning tasks can increase rates of neurogenesis (van Praag et al., 1999; Gould et al., 1999). Finally, production of inflammation in the central nervous system can produce both learning and memory deficits and reductions in neurogenesis, both of which can be attenuated by nonsteroidal anti-inflammatory agents (HaussWegrzyniak et al., 1999; Monje et al., 2003; Ekdahl et al., 2003). Thus, there are good correlations between neurogenesis and learning and memory in a number of conditions. A more vexing issue has concerned the role of new neurons in the formation of memories. Shors et al. (2001) found that inhibiting the formation of new neurons with an antimitotic chemical caused impairment in trace eyeblink conditioning (a hippocampus dependent task) but not delay eyeblink conditioning (a hippocampus independent task). An alternative to antimitotic agents is to focally irradiate the adult hippocampus, causing a dramatic and long lasting reduction in hippocampal neurogenesis. This manipulation also impairs hippocampusdependent learning and memory performance, while not impacting tasks less dependent on hippocampal activity (Madsen et al., 2003; Rola et al., 2004; Raber et al., 2004). However, not all hippocampal tasks are impacted by focal irradiation (see discussion by Leuner et al., 2006). This author feels part of the problem may be that recently born, naive, uncommitted neurons are needed for learning new tasks, and that a slowly diminishing
The role of accumulations of the Aβ peptide in causing memory disturbance of APP mice has received considerable attention in the past decade. Very early in their study, APP transgenic mice were found to have cognitive deficits (Hsiao et al., 1996; Holcomb et al., 1998), and the degree of mnemonic impairment was correlated with the extent of Aβ accumulation in individual animals (Dodart et al., 1999; Chen et al., 2000; Gordon et al., 2001). Our group was the first to show that reducing the amyloid deposition (in this case with vaccination) also reduced the behavioral phenotype in the APP transgenic mice (Morgan et al., 2000). While this was a comforting outcome, the association between amyloid plaques and memory disruption was challenged by observations of memory dysfunction in mice that never developed amyloid plaque pathology (Moran et al., 1995; Hsia et al., 1999; Koistinaho et al., 2001). In other circumstances, early testing of some mouse strains revealed some forms of memory disruption prior to the appearance of amyloid deposits (Holcomb et al., 1999; Westerman et al., 2002; Richardson et al., 2003; Lee et al., 2004). Importantly, the deterioration of memory function as mice aged was not linearly related to the increasing amount of Aâ in the brain (Westerman et al., 2002; Trinchese et al., 2004). One potential explanation for this nonlinear relationship between Aβ deposition and memory disruption is the presence of toxic intermediate stages of Aβ aggregates that are neither monomer, nor fully fibrillar forms. These are referred to as oligomers of Aβ or ADDLs (Walsh et al., 2002; Kayed et al., 2003; Klein et al., 2004). Recent data suggest that these intermediate sized Aβ aggregates are the best correlates of memory disturbance in the APP transgenic mouse models of amyloid deposition (Lesne et al., 2006). Nonetheless, many questions remain regarding these aggregates. Typically these aggregates are generated either in vitro or in cell culture systems. Do the same types of aggregates formed in vitro or in culture also exist in vivo? Are all the different reported intermediate aggregates actually the same, or are there important differences dependent upon how they were generated? Certainly the clarification of these issues and the definition of the in vivo role of oligomers in both the APP models of amyloid deposition and in Alzheimer patients are exciting areas of endeavor. These may be the molecular form most closely linked to the suppression of neurogenesis reported byZhang et al. (2006). The results observed by Zhang et al. with respect to neurogenesis are part of a growing list of papers showing that amyloid deposition is linked to reduced formation of new
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neurons from neural precursors born during adulthood in the subgranular layer of the dentate gyrus. Haughey et al. (2002) found reduced proliferation and differentiation of neurons in APPsw mice developed by Borchelt et al. (1997). Dong et al. (2004) also found reduced proliferation of dentate neurons in Tg2576 APP transgenic mice. Donovan et al. (2006) using PDAPP mice found reduced proliferation and survival of new neurons in the subgranular zone, but not in the outer molecular layer of the dentate (a numerically minor component of the proliferating cells). Rockenstein et al. (2007) recently reported decreased neural differentiation in mThy1-hAPP751 mice. Consistent with a role of Aβ deposits in regulating neurogenesis are reports demonstrating that removal of amyloid deposits using either immunization (Becker et al., 2007) or cerebrolysin treatment (Rockenstein et al., 2007) leads to increased neurogenesis in dentate gyrus, implying that amyloid is responsible for the reduced census of newly born neurons. The only exception to this observation of general decline of neurogenesis in amyloid depositing mice was Jin et al. (2004) using an APPsw line developed by Hsia et al. (1999). They reported increased numbers of cells at 7 days after bromodeoxyuridine injection, but did not examine longer times after the injection, which would be needed to observe differentiation and survival into neurons. Studies of mice with genetic modifications of presenilin-1, have led to mixed outcomes, but in no case did these mice deposit amyloid (Feng et al., 2001; Wen et al., 2002, 2004). Thus, in the APP transgenic mouse models, the data are largely consistent with the argument that amyloid reduces neurogenesis. Recently a series of papers have addressed the question of environmental enrichment in APP transgenic mouse models. Although the studies are not in total agreement, environmental enrichment does appear to reduce amyloid loads (Lazarov et al., 2005; Costa et al., 2006; Ambree et al., 2006) and to improve cognitive performance (Jankowsky et al., 2005; Costa et al., 2006). Most recently Wolf et al. (2006) contrasted the effects of environmental enrichment with simple increases in physical activity on neurogenesis in the APP-23 mouse model of amyloid deposition. They found that enrichment increases neurogenesis and protects from memory impairments in APP mice. However, physical activity alone achieves neither increased neurogenesis nor protection from memory impairment. Coupled with the results showing that Aβ reduces neurogenesis in APP mice from Zhang et al. (2006), these data link this reduction in neurogenesis to the cognitive impairments in amyloid depositing mice. Memory Deficits in Alzheimer's Disease A broader question is with regard to linkage of changes in the murine models to Alzheimer's disease. In general, the most striking feature of the multiple well characterized APP transgenic mouse models is how similar they are. All show a progressive accumulation of Aβ deposits over the lifespan and these appear first and most intensely in the hippocampus and dorsal and anterior cortices (Games et al., 1995; Hsiao et al., 1996; Borchelt et al., 1997; Sturchler-Pierrat et al., 1997;
Holcomb et al., 1998; Janus et al., 2000). These deposits include both diffuse deposits and compacted plaques stained by Congo red, Thioflavin S and surrounded by dystrophic neurites (Gordon et al., 2002). All develop glial reactions surrounding the compacted deposits and have elevated levels of markers for inflammation (Morgan et al., 2005). These features of amyloid deposition are virtually identical to those found in Alzheimer tissue postmortem, and generally the same in all the mice irrespective of the APP mutation or the promoter used to drive expression of the transgene. Even the histological distribution of Aβ40 and Aβ42 is similar to that found in the Alzheimer tissue, with Aβ40 in vascular deposits and compacted deposits and Aβ42 in diffuse deposits and compacted deposits (Gordon et al., 2002). Thus, they are excellent reproductions of amyloid deposition in Alzheimer brain, and are valid systems in which to address scientific questions relating to that process. In general, the differences between the different models are unlikely to interfere with generalizing from one such model to another. Nonetheless, there are important features of Alzheimer's disease which are absent in these models. With the exception of the triple transgenic model (Oddo et al., 2003), none of the models have both amyloid deposits and fibrillar aggregations of hyperphosphorylated tau (neurofibrillary tangles). Perhaps most importantly, there is no widespread neuron loss in hippocampus or cortex (Irizarry et al., 1997; Calhoun et al., 1998; Takeuchi et al., 2000). This contrasts with the degeneration found in the Alzheimer brain which is so profound that it ultimately causes the death of the individual. Beyond memory and cognitive functions, even basic neural functions are lost such as bowel and bladder control and reflexes such as coughing, leading patients drown in their pulmonary secretions. The question that arises is whether the learning and memory impairments that develop in these mice are analogous to those found in Alzheimer patients. While the linkage to at least some form of amyloid production is very strong for the murine impairments, it is unclear if this has a counterpart in the Alzheimer brain. One difference is that the transgenic mice do not progress to the profound neural dysfunction found in Alzheimer patients. While there is accelerated mortality early in life of APP transgenics (Carlson et al., 1997) we find that this excess attrition abates by 12 months when amyloid deposits are building up. We find that after APP mice reach mid life, their survival rivals that of nontransgenic littermates, with mice easily reaching 28 months (Wilcock et al., 2004). Thus the cognitive disturbance in the APP mice is not as progressive or life threatening as in Alzheimer's. Some have speculated that the memory loss in these mice probably resembles that of very early stage Alzheimer patients or, perhaps, individuals with mild cognitive impairment. However, even for individuals in these incipient stages, postmortem analysis finds considerable neuron and synapse loss (Morris and Price, 2001), most probably accounting for the cognitive changes. A final concern about a role for amyloid per se in causing the cognitive deterioration in Alzheimer cases is the so-called high plaque normals; cases that come to autopsy with a full load of amyloid, but have no symptoms of dementia
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(Crystal et al., 1988; Davis et al., 1999; Knopman et al., 2003). Intriguingly, one report claims that these high plaque normal cases differ from Alzheimer cases in that they lack the inflammatory reactions (Lue et al., 1996). Given the observation that some inflammatory processes are present in the mice studied by Zhang et al. (2006), this may be the common factor associated with cognitive disruption. In conclusion, hippocampal neurogenesis appears to have some role in memory formation, but the exact nature of that role is not yet clear. Memory loss in mouse models of amyloid deposition is quite consistent, but its relevance to the cognitive deterioration found in Alzheimer patients is also unclear. Nonetheless, the strong evidence that amyloid can suppress neurogenesis, and that other manipulations that impact neurogenesis can also modify memory in APP transgenic mice, strongly points to this as an intriguing link in the steps leading from amyloid formation to memory disruption in transgenic mice, and possibly in Alzheimer patients. Acknowledgments D.M. is supported by the following awards from NIH: AG04418, AG15490, AG 18478, AG25509, AG 25711 and NS 48335. References Ambree, O., Leimer, U., Herring, A., Gortz, N., Sachser, N., Heneka, M.T., Paulus, W., Keyvani, K., 2006. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am. J. Pathol. 169, 544–552. Becker, M., Lavie, V., Solomon, B., 2007. Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 104, 1691–1696. Borchelt, D.R., Ratovitski, T., Van Lare, J., Lee, M.K., Gonzales, V., Jenkins, N.A., Copeland, N.G., Price, D.L., Sisodia, S.S., 1997. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor protein. Neuron 19, 939–945. Calhoun, M.E., Wiederhold, K.H., Abramowski, D., Phinney, A.L., Probst, A., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., Jucker, M., 1998. Neuron loss in APP transgenic mice [letter]. Nature 395, 755–756. Carlson, G.A., Borchelt, D.R., Dake, A., Turner, S., Danielson, V., Coffin, J.D., Eckman, C., Meiners, J., Nilsen, S., Younkin, S.G., Hsiao, K., 1997. Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum. Mol. Genet. 6 (11), 1951–1959. Chen, G., Chen, K.S., Knox, J., Inglis, J., Bernard, A., Martin, S.J., Justice, A., McConlogue, L., Games, D., Freedman, S.B., Morris, R.G., 2000. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408, 975–979. Christie, B.R., Cameron, H.A., 2006. Neurogenesis in the adult hippocampus. Hippocampus 16, 199–207. Costa, D.A., Cracchiolo, J.R., Bachstetter, A.D., Hughes, T.F., Bales, K.R., Paul, S.M., Mervis, R.F., Arendash, G.W., Potter, H., 2006. Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms. Neurobiol. Aging. Crystal, H., Dickson, D., Fuld, P., Masur, D., Scott, R., Mehler, M., Masdeu, J., Kawas, C., Aronson, M., Wolfson, L., 1988. Clinico-pathological studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 38, 1682–1687. Davis, D.G., Schmitt, F.A., Wekstein, D.R., Markesbery, W.R., 1999. Alzheimer neuropathologic alterations in aged cognitively normal subjects. J. Neuropathol. Exp. Neurol. 58, 376–388.
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