Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration

Saura, Carlos A.; Choi, Se‐Young; Beglopoulos, Vassilios; Malkani, Seema; Zhang, Dawei; Rao, B.S. Shankaranarayana; Chattarji, Sumantra; Kelleher, Raymond J.; Kandel, Eric R.; Duff, Karen; Kirkwood, Alfredo; Shen, Jie

doi:10.1016/s0896-6273(04)00182-5

Cited by 690 publications

(796 citation statements)

References 53 publications

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“…Recently, it has been found that knockout of PS1 and PS2 in the mouse is able to trigger robust neurodegeneration in the brain (Feng, et al, 2004, Saura, et al, 2004. We have provided further evidence to show that this neurodegeneration is featured by many characteristics of AD neurodegeneration, including the presences of NFTs, the increased tau hyperphosphorylation, and the presence of intracellular filamentous aggregates (submitted results).…”

Section: Discussionsupporting

confidence: 60%

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: Discussionsupporting

confidence: 60%

Adult neurogenesis is functionally associated with AD-like neurodegeneration

Chen

Nakajima

Choi

et al. 2008

Neurobiology of Disease

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“…In addition, the genes encoding presenilins PS1 and PS2 have also been associated with CBP dysfunctions in specific cortical regions; the deletion of these two genes leads to a reduction of CBP protein and mRNA levels in both the cytoplasm and nucleus of cortical cells, whereas the total and phosphorylated forms of CREB remain unchanged. As a consequence, the genes regulated through the CREB/CBP complex are partially repressed [152]. This study suggests a positive regulation of CBP expression through presenilins.…”

Section: Ad and Related Diseasesmentioning

confidence: 67%

“…This study suggests a positive regulation of CBP expression through presenilins. Interestingly, these conditional PS1 −/− / PS2 −/− mutants presented a decreased long-term potentiation (LTP), associated with long-term memory (LTM) deficits and hyperphosphorylated tau [152]. Thus, the effect of PS absence clearly alters the CBP-dependent pathway, and the effect of FAD-associated PS mutations remains unknown.…”

Section: Ad and Related Diseasesmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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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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Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration

Cited by 690 publications

References 53 publications

Adult neurogenesis is functionally associated with AD-like neurodegeneration

Adult neurogenesis is functionally associated with AD-like neurodegeneration

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

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