Dataset Information

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

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.

SUBMITTER: Confettura AD

PROVIDER: S-EPMC8734066 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Confettura Alessandro Dario AD Cuboni Eleonora E Ammar Mohamed Rafeet MR Jia Shaobo S Gomes Guilherme M GM Yuanxiang PingAn P Raman Rajeev R Li Tingting T Grochowska Katarzyna M KM Ahrends Robert R Karpova Anna A Dityatev Alexander A Kreutz Michael R MR

Translational neurodegeneration 20220106 1

<h4>Background</h4>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.<h4>Methods</h4>We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging ...[more]

PMID: 34986876

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Project description:BackgroundActivating the ubiquitin-proteasome system to dismantle disease- related proteins such as tau, β-amyloid, APP, and α-synuclein is an important focus in the research of neurodegenerative proteinopathy. By analyzing the serum RNA extracted from wild-type and Alzheimer's disease (AD) transgenic mice at different ages (4, 8, and 12 months), this study revealed a new protective role of FBXL16 in AD, primarily through facilitating the degradation of disease-related proteins via the ubiquitin proteasome system.MethodsProteomic analysis were conducted using protein lysates from HEK293 cells overexpressing FBXL16 to identify potential interacting proteins that interact with FBXL16. Subsequent experiments demonstrated that FBXL16 promotes the proteasomal degradation of the APP protein, as evidenced by co-immunoprecipitation with MG132 and cycloheximide (CHX), immunohistochemistry (IHC) and immunocytochemistry (ICC). Memory and cognitive improvements were observed in 3×Tg AD mice through the use of a lentivirus-mediated approach to generate a brain-specific AD mouse model overexpressing FBXL16 via stereotaxic injection. Furthermore, a brain-specific conditional knockout (cko) FBXL16 mouse model was generated and employed to further confirm the functional role of FBXL 16 in AD via various behavioral tests including Morris water maze and Y-maze.ResultsThe level of FBXL16 in the brains of transgenic APP/PSEN mice with AD decreased with age. Accelerated degradation of APP was observed when FBXL16 was overexpressed in the hippocampi of these AD mice via a lentivirus. This process led to notable improvements in cognitive impairments and reductions in neuroinflammation. Further studies using proteomics and bioinformatics techniques identified transcription factors and binding proteins associated with FBXL16, providing deeper insights into the potential role of FBXL16 in the regulation of AD. Finally, the in vivo effects of FBXL16 deficiency were further substantiated in cko mice, which overexpress Aβ but specifically lack FBXL16 in the brain region.ConclusionsThese findings suggest that FBXL16 could be a new regulator of AD. These findings provide a foundation for further research into drug development and potential therapeutic strategies to combat other related neurodegenerative proteinopathies.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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