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.
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This post is Copyright: 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 | December 29, 2024