A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer's disease
© 2023. The Author(s)..
Many aging individuals accumulate the pathology of Alzheimer's disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid β-protein (Aβ) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with β-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aβ deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aβ and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
|---|---|
| Enthalten in: |
Nature communications - 14(2023), 1 vom: 02. Nov., Seite 7030 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Aron, Liviu [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Amyloid beta-Peptides |
|---|
| Anmerkungen: |
Date Completed 09.11.2023 Date Revised 17.02.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41467-023-42704-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364111518 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364111518 | ||
| 003 | DE-627 | ||
| 005 | 20240217232237.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-023-42704-6 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1297.xml |
| 035 | |a (DE-627)NLM364111518 | ||
| 035 | |a (NLM)37919281 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Aron, Liviu |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer's disease |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.11.2023 | ||
| 500 | |a Date Revised 17.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a Many aging individuals accumulate the pathology of Alzheimer's disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid β-protein (Aβ) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with β-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aβ deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aβ and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a tau Proteins |2 NLM | |
| 650 | 7 | |a RE1-silencing transcription factor |2 NLM | |
| 700 | 1 | |a Qiu, Chenxi |e verfasserin |4 aut | |
| 700 | 1 | |a Ngian, Zhen Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Marianna |e verfasserin |4 aut | |
| 700 | 1 | |a Drake, Derek |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Jaejoon |e verfasserin |4 aut | |
| 700 | 1 | |a Fernandez, Marty A |e verfasserin |4 aut | |
| 700 | 1 | |a Roche, Perle |e verfasserin |4 aut | |
| 700 | 1 | |a Bunting, Emma L |e verfasserin |4 aut | |
| 700 | 1 | |a Lacey, Ella K |e verfasserin |4 aut | |
| 700 | 1 | |a Hamplova, Sara E |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Monlan |e verfasserin |4 aut | |
| 700 | 1 | |a Wolfe, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a Bennett, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Eunjung A |e verfasserin |4 aut | |
| 700 | 1 | |a Yankner, Bruce A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 14(2023), 1 vom: 02. Nov., Seite 7030 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
| 773 | 1 | 8 | |g volume:14 |g year:2023 |g number:1 |g day:02 |g month:11 |g pages:7030 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-023-42704-6 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 14 |j 2023 |e 1 |b 02 |c 11 |h 7030 | ||