RTN4B‐mediated suppression of Sirtuin 2 activity ameliorates β‐amyloid pathology and cognitive impairment in Alzheimer's disease mouse model

Sirtuin 2 (SIRT2) is an NAD+ dependent deacetylase that is the most abundant sirtuin protein in the brain. Accumulating evidence revealed the role of SIRT2 in a wide range of biological processes and age‐related diseases. However, the pivotal mechanism of SIRT2 played in Alzheimer's disease (AD...

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Published in:Aging cell 2020-08, Vol.19 (8), p.e13194-n/a
Main Authors: Wang, Yan, Yang, Jing‐Qi, Hong, Ting-Ting, Sun, Yuan‐Hong, Huang, Hai‐Li, Chen, Feng, Chen, Xiong‐Jin, Chen, Hui‐Yi, Dong, Shan‐Shan, Cui, Li‐Li, Yang, Tie‐Lin
Format: Article
Language:English
Subjects:
Acetylation
Advertising executives
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Amyloid precursor protein
Amyloid Precursor Protein Secretases - metabolism
Analysis
Animals
Antibodies
APP/PS1 transgenic mice
Aspartic Acid Endopeptidases - metabolism
BACE1
Cognition & reasoning
Cognitive ability
Cognitive Dysfunction - metabolism
Cognitive Dysfunction - pathology
Deacetylation
Disease Models, Animal
Genetic engineering
HEK293 Cells
Hippocampus
Hippocampus - metabolism
Hippocampus - pathology
Humans
Male
Mass spectrometry
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
NAD
Neurodegenerative diseases
Neurons - metabolism
Neurons - pathology
Nogo Proteins - metabolism
Original
Pathology
Plasmids
Presenilin 1
Protein Isoforms
Proteins
Rodents
RTN4B
Scientific imaging
Sirtuin 2
Sirtuin 2 - antagonists & inhibitors
Sirtuin 2 - metabolism
Target marketing
Transgenic mice
Ubiquitination
β-Site APP-cleaving enzyme 1
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Summary:Sirtuin 2 (SIRT2) is an NAD+ dependent deacetylase that is the most abundant sirtuin protein in the brain. Accumulating evidence revealed the role of SIRT2 in a wide range of biological processes and age‐related diseases. However, the pivotal mechanism of SIRT2 played in Alzheimer's disease (AD) remains unknown. Here, we report that pharmacological inactivation of SIRT2 has a beneficial effect in AD. The deacetylase inhibitor of SIRT2 rescued the cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mouse (APP/PS1 mouse), and the BACE1 cleavage was weakened to reduce the β‐amyloid (Aβ) production in the hippocampus. Moreover, we firstly identified that Reticulon 4B (RTN4B) played a crucial role between SIRT2/BACE1 regulation in AD. RTN4B, as a deacetylation substrate for SIRT2, the deacetylation by SIRT2 drived the ubiquitination and degradation of RTN4B and then the disturbed RTN4B interacted with and influenced the expression of BACE1. When we overexpressed RTN4B in neurons of the hippocampus in the AD mouse model, the abnormal Aβ accumulation and cognitive impairment were ameliorated, consistent with the results of SIRT2 inhibition in vivo. Moreover, we showed that the regulatory effect of SIRT2 on BACE1 is dependent on RTN4B. When RTN4B was knocked down, the effects of SIRT2 inhibition on the BACE1 level, Aβ pathology, and AD‐liked behaviors were also blocked. Collectively, we provide evidence that SIRT2 may be a potential target for AD; the new found SIRT2/RTN4B/BACE1 pathological pathway is one of the critical mechanisms for the improvement of SIRT2 on AD. The repression of SIRT2 deacetylase activity could ameliorate Aβ pathology and cognitive deficits in the Alzheimer's Disease (AD) mouse model. As for the mechanism, SIRT2 influences the β‐secretase 1 (BACE1) by directly deacetylates reticulon 4B protein (RTN4B), thus affect the production of Aβ, finally contribute to the AD progress. These data marked that SIRT2/RTN4B/BACE1 is a new critical pathological pathway in recusing AD.
ISSN:1474-9718
1474-9726
DOI:10.1111/acel.13194