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TitleREST and stress resistance in ageing and Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsLu, T, Aron, L, Zullo, J, Pan, Y, Kim, H, Chen, Y, Yang, T-H, Kim, H-M, Drake, D, X Liu, S, Bennett, DA, Colaiácovo, MP, Yankner, BA
JournalNature
Volume507
Issue7493
Pagination448-54
Date Published2014 Mar 27
ISSN1476-4687
KeywordsAged, Aged, 80 and over, Aging, Alzheimer Disease, Amyloid beta-Peptides, Animals, Autophagy, Brain, Caenorhabditis elegans Proteins, Cell Death, Cell Nucleus, Chromatin Immunoprecipitation, Cognition, DNA-Binding Proteins, Down-Regulation, Frontotemporal Dementia, Gene Expression Regulation, Humans, Lewy Body Disease, Longevity, Mice, Mild Cognitive Impairment, Neurons, Neuroprotective Agents, Oxidative Stress, Phagosomes, Repressor Proteins, Transcription Factors, Up-Regulation, Wnt Signaling Pathway, Young Adult
Abstract

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

DOI10.1038/nature13163
Alternate JournalNature
PubMed ID24670762
PubMed Central IDPMC4110979
Grant ListDP1 AG044161 / AG / NIA NIH HHS / United States
DP1 OD006849 / OD / NIH HHS / United States
DP1OD006849 / OD / NIH HHS / United States
P01 AG027916 / AG / NIA NIH HHS / United States
P01AG27916 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 AG026651 / AG / NIA NIH HHS / United States
R01 GM105853 / GM / NIGMS NIH HHS / United States
R01AG15819 / AG / NIA NIH HHS / United States
R01AG17917 / AG / NIA NIH HHS / United States
R01AG26651 / AG / NIA NIH HHS / United States
R01GM072551 / GM / NIGMS NIH HHS / United States
T32 AG000222 / AG / NIA NIH HHS / United States
Top50 Topics: 
Amyloid beta, Oxidative stress
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Source URL: https://www.j-alz.com/content/rest-and-stress-resistance-ageing-and-alzheimers-disease