Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory

Bonds, Jacqueline A.; Kuttner-Hirshler, Yafit; Bartolotti, Nancy; Tobin, Matthew K.; Pizzi, Michael; Marr, Robert A.; Lazarov, Orly

doi:10.1371/journal.pone.0131266

Cited by 32 publications

(38 citation statements)

References 43 publications

(55 reference statements)

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“…Interestingly, BACE1 has been previously shown to modulate CREB signaling independent of amyloid, offering another potential mechanism underlying CREB deficits [17]. In addition, several studies suggest that PS1 itself regulates CREB expression and function [13,24,56,57]. It is yet to be elucidated whether one or more pathways is sufficient or necessary for the rescue of CREB and memory deficit.…”

Section: Discussionmentioning

confidence: 99%

Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer’s Disease Mice

Bartolotti

Segura

Lazarov

2016

JAD

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The mechanism underlying impaired learning and memory in Alzheimer's disease is not fully elucidated. The phosphorylation of cyclic-AMP response element binding protein (pCREB) in the hippocampus is thought to be a critical initiating step in the formation of long-term memories. Here, we tested CRE-driven gene expression following learning in mice harboring the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mutations using CRE-β galactosidase reporter. We show that young adult APPswe/PS1ΔE9 mice exhibit impaired recognition memory and reduced levels of pCREB, and its cofactors CREB binding protein (CBP) and p-300 following a learning task, compared to their wild type littermate counterparts. Impairments in learning-induced activation of CREB in these mice are manifested by reduced CRE-driven gene transcription. Importantly, expression of the CRE-driven immediate early gene, Egr-1 (Zif268) is decreased in the CA1 region of the hippocampus. These studies implicate defective CREB-dependent plasticity in the mechanism underlying learning and memory deficits in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer’s Disease Mice

Bartolotti

Segura

Lazarov

2016

JAD

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“…It has been known that PSEN1 is required for neurodevelopment and differentiation, as lack of Psen1 causes premature NPC differentiation 116 . Loss of Psen1 also induces learning and memory deficits in mice that appear to owe to impaired adult hippocampal neurogenesis 117 . Promoter DNA methylation, in coordination with H3K9 acetylation, controls the expression of Psen1 in the cerebral cortex during development 118 .…”

Section: Epigenetic Dysregulation In Brain Disordersmentioning

confidence: 99%

Epigenetic mechanisms in neurogenesis

et al. 2016

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In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. Epigenetic mechanisms — including DNA and histone modifications, as well as regulation by non-coding RNAs — have pivotal roles in different stages of neurogenesis. Aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. Here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified DNA cytosine modifications. We also briefly cover the emerging field of epitranscriptomics, which involves modifications of mRNAs and long non-coding RNAs.

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“…Also, by knocking-in PS1 familial mutations or using a transgenic mouse expressing a chimeric human-mouse version of APP with the Swedish mutation, a severe and well studied familial mutant, researchers observed a decrease neural proliferation (Haughey et al, 2002; Wang et al, 2004). Many groups have seen a similar effect with other PS1-dependent AD mouse models, including PS1 mutants and PS1 knock downs (Bonds et al, 2015; Choi et al, 2008; Demars et al, 2010; Donovan et al, 2006; Rodriguez et al, 2008; Wen et al, 2004; Zhang et al, 2007). Conditional knock-out of PS1 in forebrain alone is enough to reduce neurogenesis (Saura et al, 2005), highlighting the importance of PS1 in the maintenance of neural stem cells.…”

Section: Notch and Neural Stem Cellsmentioning

confidence: 68%

Physiological and pathological roles of the γ-secretase complex

Carroll

2016

Brain Research Bulletin

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Gamma-secretase (GS) is an enzyme complex that cleaves numerous substrates, and it is best known for cleaving amyloid precursor protein (APP) to form amyloid-beta (Aβ peptides. Aberrant cleavage of APP can lead to Alzheimer’s disease, so much research has been done to better understand GS structure and function in hopes of developing therapeutics for Alzheimer’s. Therefore, most of the attention in this field has been focused on developing modulators that reduce pathogenic forms of Aβ while leaving Notch and other GS substrates intact, but GS provides multiple avenues of modulation that could improve AD pathology. GS has complex regulation, through its essential subunits and other associated proteins, providing other targets for AD drugs. Therapeutics can also alter GS trafficking and thereby improve cognition, or move beyond Aβ entirely, effecting Notch and neural stem cells. GS also cleaves substrates that affect synaptic morphology and function, presenting another window by which GS modulation could improve AD pathology. Taken together, GS presents a unique cross road for neural processes and an ideal target for AD therapeutics.

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Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory

Cited by 32 publications

References 43 publications

Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer’s Disease Mice

Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer’s Disease Mice

Epigenetic mechanisms in neurogenesis

Physiological and pathological roles of the γ-secretase complex

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