Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer's disease

TY - JOUR

T1 - Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer's disease

AU - Confettura, Alessandro Dario

AU - Cuboni, Eleonora

AU - Ammar, Mohamed Rafeet

AU - Jia, Shaobo

AU - Gomes, Guilherme M

AU - Yuanxiang, PingAn

AU - Raman, Rajeev

AU - Li, Tingting

AU - Grochowska, Katarzyna M

AU - Ahrends, Robert

AU - Karpova, Anna

AU - Dityatev, Alexander

AU - Kreutz, Michael R

N1 - © 2022. The Author(s).

PY - 2022/1/6

Y1 - 2022/1/6

N2 - 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.

AB - 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.

U2 - 10.1186/s40035-021-00277-8

DO - 10.1186/s40035-021-00277-8

M3 - SCORING: Journal article

C2 - 34986876

VL - 11

JO - TRANSL NEURODEGENER

JF - TRANSL NEURODEGENER

SN - 2047-9158

IS - 1

M1 - 2

ER -