Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer's disease.
Alzheimer's disease
Amyloid-β
Cullins
IRS1
Insulin
MLN-4924
Metabolic syndrome
Neddylation
TNFα
Journal
Translational neurodegeneration
ISSN: 2047-9158
Titre abrégé: Transl Neurodegener
Pays: England
ID NLM: 101591861
Informations de publication
Date de publication:
06 01 2022
06 01 2022
Historique:
received:
17
09
2021
accepted:
24
12
2021
entrez:
6
1
2022
pubmed:
7
1
2022
medline:
5
4
2022
Statut:
epublish
Résumé
The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown. We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms. We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'. Collectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.
Sections du résumé
BACKGROUND
The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown.
METHODS
We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms.
RESULTS
We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'.
CONCLUSIONS
Collectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.
Identifiants
pubmed: 34986876
doi: 10.1186/s40035-021-00277-8
pii: 10.1186/s40035-021-00277-8
pmc: PMC8734066
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2Informations de copyright
© 2022. The Author(s).
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