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.
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.
Original language | English |
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Article number | 2 |
Number of pages | 18 |
Journal | Translational neurodegeneration |
Volume | 11 |
Issue number | 1 |
DOIs | |
Publication status | Published - 6 Jan 2022 |
Austrian Fields of Science 2012
- 301407 Neurophysiology
- 301403 Neurochemistry
- 301402 Neurobiology
Keywords
- Metabolic syndrome
- Alzheimer's disease
- Neddylation
- Cullins
- MLN-4924
- Insulin
- IRS1
- Amyloid-beta
- TNF alpha
- BETA-AMYLOID OLIGOMERS
- LONG-TERM DEPRESSION
- RECEPTOR SUBSTRATE 1
- DIABETES-MELLITUS
- NEDD8-ACTIVATING ENZYME
- METABOLIC SYNDROME
- A-BETA
- BRAIN
- MICE
- HYPOTHESIS
- TNFα
- Amyloid-β