Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer\u2019s disease

Alessandro Dario Confettura,Eleonora Cuboni,Robert Ahrends,Shaobo Jia,Pingan Yuanxiang,Rajeev Raman,Tingting Li,Mohamed Rafeet Ammar,Guilherme M Gomes,Michael R Kreutz,Katarzyna M Grochowska,Alexander Dityatev,Anna Karpova

doi:10.1186/s40035-021-00277-8

Abstract

BackgroundThe 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.MethodsWe 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.ResultsWe 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'.ConclusionsCollectively, 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.

Highlights

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
Following the activation of tumor necrosis factor-α (TNFα) receptor 1, stress kinases such as c-Jun N-terminal kinase (JNK) and IκB kinase induce serine phosphorylation of insulin receptor substrate 1 (IRS1) [35] and this has been strongly linked to insulin resistance (IR) and impaired insulin signaling in neurons [36]
Cells were incubated with 100 nM insulin and 10 ng/ml TNFα for 24 h followed by acute stimulation with insulin for 15 min to test for insulin responsiveness (Fig. 1a)

Summary

Introduction

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 suggested that IR and amyloid-β (Aβ) pathology interact functionally in Alzheimer’s disease (AD) [10, 17,18,19] and that their interaction might cause worsening of AD symptoms This notion is based on several unknowns. The underpinnings of the molecular interplay between IR and Aβ pathology are, for instance, not well understood, in part because the topology and regulation of synaptic insulin signaling pathways are not well investigated Along these lines, the mechanisms underlying synaptic IR are not entirely clear yet

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Discussion

Conclusion