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

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

Publications: Contribution to journalArticlePeer Reviewed

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.
Original languageEnglish
Article number2
Number of pages18
JournalTranslational neurodegeneration
Volume11
Issue number1
DOIs
Publication statusPublished - 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

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