Brain Phosphoproteomic Analysis Identifies Diabetes-related Substrates in Alzheimer's Disease Pathology in Older Adults

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2024 Dec 28

PMID 39732516

Authors

Ana W Capuano

Vishal Sarsani

Shinya Tasaki

Rupal I Mehta

Jun Li

Rexford Ahima

Steven Arnold

David A Bennett

Vladislav Petyuk

Liming Liang

Zoe Arvanitakis

Affiliations

Soon will be listed here.

Abstract

Introduction: Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored.

Methods: We performed tandem mass tag-based phosphoproteome profiling in post mortem human brain prefrontal cortex samples from 191 deceased older adults with and without diabetes and pathologic AD.

Results: Among 7874 quantified phosphosites, microtubule-associated protein tau (MAPT) phosphorylated at T529 and T534 (isoform 8 T212 and T217) were more abundant in AD and showed differential associations with diabetes. Network analysis of co-abundance patterns uncovered synergistic interactions between AD and diabetes, with one module exhibiting higher MAPT phosphorylation (15 MAPT phosphosites) and another displaying lower MAP1B phosphorylation (22 MAP1B phosphosites).

Discussion: This study offers phosphoproteomics insights into AD in diabetes, shedding light on mechanisms that can inform the development of therapeutics for dementia.

Highlights: The risk of Alzheimer's disease (AD) dementia is increased among older adults living with diabetes. The patterns of AD-related phosphoprotein in the human brain in older adults are differential among older adults living with diabetes. Microtubule-associated protein tau phosphorylated at T529 and T534 (isoform 8 T212 and T217) showed differential associations with diabetes. Phosphosite co-abundance networks of synergistic interactions between AD and diabetes were identified.

Citing Articles

Brain phosphoproteomic analysis identifies diabetes-related substrates in Alzheimer's disease pathology in older adults.

Capuano A, Sarsani V, Tasaki S, Mehta R, Li J, Ahima R Alzheimers Dement. 2024; 21(2):e14460.

PMID: 39732516 PMC: 11848201. DOI: 10.1002/alz.14460.

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