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- Title
Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer's disease.
- Authors
Confettura, Alessandro Dario; Cuboni, Eleonora; Ammar, Mohamed Rafeet; Jia, Shaobo; Gomes, Guilherme M.; Yuanxiang, PingAn; Raman, Rajeev; Li, Tingting; Grochowska, Katarzyna M.; Ahrends, Robert; Karpova, Anna; Dityatev, Alexander; Kreutz, Michael R.
- Abstract
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.
- Subjects
WESTERN diet; ANIMAL models for aging; INSULIN resistance; ALZHEIMER'S disease; PROTEOLYSIS; DISEASE risk factors; NEUROINFLAMMATION; UNHEALTHY lifestyles
- Publication
Translational Neurodegeneration, 2022, Vol 11, Issue 1, p1
- ISSN
2047-9158
- Publication type
Article
- DOI
10.1186/s40035-021-00277-8