The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice

Wen, Paul; Hof, Patrick R.; Chen, Xiaoping; Gluck, Karen; Austin, Gregory L.; Younkin, Steven G.; Younkin, Linda H.; DeGasperi, Rita; Sosa, Miguel A. Gama; Robakis, Nikolaos K.; Haroutunian, Vahram; Elder, Gregory A.

doi:10.1016/j.expneurol.2004.04.002

Cited by 173 publications

(130 citation statements)

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“…Overall, the findings in those models were inconsistent. For example, in transgenic/knock-in mice expressing mutant PS1, mutant APP, or both, neurogenesis in the brain was impaired , Wen, et al, 2004, Chevallier, et al, 2005, Donovan, et al, 2006, Zhang, et al, 2007 or enhanced (Jin, et al, 2004b, Greenberg andJin, 2007). The reasons that led to this discrepancy among those different transgenic or knock-in mouse strains or between those studies and ours are not clear.…”

Section: Discussionmentioning

confidence: 57%

Adult neurogenesis is functionally associated with AD-like neurodegeneration

Chen

Nakajima

Choi

et al. 2008

Neurobiology of Disease

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Alzheimer's disease (AD) is predominantly characterized by progressive neuronal loss in the brain. It has been recently found that adult neurogenesis in the hippocampal dentate gyrus of AD patients is significantly enhanced, while its functional significance is still unknown. By using an AD-like neurodegeneration mouse model, we show here that neurogenesis in the dentate gyrus was neurodegenerative stage-dependent. At early stages of neurodegeneration, neurogenesis was significantly enhanced and newly generated neurons migrated into the local neuronal network. Up to late stages of neurodegeneration, however, the survival of newly generated neurons was impaired so that the enhanced neurogenesis could not be detected any more. Most interestingly, these dynamic changes in neurogenesis were correlated with the severity of neuronal loss in the dentate gyrus, indicating that neurogenesis may work as a self-repairing mechanism to compensate for neurodegeneration. Therefore, to enhance endogenous neurogenesis at early stages of neurodegeneration may be a valuable strategy to delay neurodegenerative progress.

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Section: Discussionmentioning

confidence: 57%

Adult neurogenesis is functionally associated with AD-like neurodegeneration

Chen

Nakajima

Choi

et al. 2008

Neurobiology of Disease

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“…Presenilin also affects β-catenin signalling which then helps regulate the cell cycle [2], a process that could be disrupted by PS over expression or mutation. Finally, under or over-expressed or mutant presenilins inhibit the cell cycle [15,16], increase cells' sensitivity to apoptosis [6,10,43,44,48] and, in transgenic mice, results in age-related neurodegeneration [3,36] and reduced neurogenesis [9,45,46,51]. All of these effects would be a natural consequence of aneuploidy activating the mitotic cell cycle checkpoint.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Boeras

Granic

Padmanabhan

et al. 2008

Neurobiology of Aging

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Mutations in the presenilin 1 gene cause most early-onset familial Alzheimer's disease (FAD). Here we report that a defect in the cell cycle-improper chromosome segregation-can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: 1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knockin mice are aneuploid by metaphase chromosome analysis and in situ hybridization, 2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 hours, including trisomy 21. 3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer's disease are discussed.

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“…Evidence suggests that these Ab species may also alter NPC proliferation depending on the time and type of animal models used. 8,[12][13][14] We hypothesized that the discrepancy in animal models may reflect the existence of different levels of soluble Ab40 and/or Ab42 in each animal model. Another less-likely factor might be that a relatively small number of stem cells were normally examined in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…11 Similar impairment in neurogenesis was observed in several transgenic mouse models expressing presenilin-1 (PS1) familial AD mutants. [12][13][14] The underlying mechanisms of altered neurogenesis are not clear in these animal models. It is anticipated that human studies using postmortem brains are even more complicated to interpret.…”

mentioning

confidence: 99%