Metabolic stress and age drive inflammation and cognitive decline in mice and humans

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-03-20 DOI:10.1002/alz.70060

Sarah E. Elzinga, Kai Guo, Ali Turfah, Rosemary E. Henn, Ian F. Webber-Davis, John M. Hayes, Crystal M. Pacut, Samuel J. Teener, Andrew D. Carter, Diana M. Rigan, Adam M. Allouch, Dae-Gyu Jang, Rachel Parent, Emily Glass, Geoffrey G. Murphy, Stephen I. Lentz, Kevin S. Chen, Lili Zhao, Junguk Hur, Eva L. Feldman

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引用次数: 0

Abstract

INTRODUCTION

Metabolic stressors (obesity, metabolic syndrome, prediabetes, and type 2 diabetes [T2D]) increase the risk of cognitive impairment (CI), including Alzheimer's disease (AD). Immune system dysregulation and inflammation, particularly microglial mediated, may underlie this risk, but mechanisms remain unclear.

METHODS

Using a high-fat diet-fed (HFD) model, we assessed longitudinal metabolism and cognition, and terminal inflammation and brain spatial transcriptomics. Additionally, we performed hippocampal spatial transcriptomics and single-cell RNA sequencing of post mortem tissue from AD and T2D human subjects versus controls.

RESULTS

HFD induced progressive metabolic and CI with terminal inflammatory changes, and dysmetabolic, neurodegenerative, and inflammatory gene expression profiles, particularly in microglia. AD and T2D human subjects had similar gene expression changes, including in secreted phosphoprotein 1 (SPP1), a pro-inflammatory gene associated with AD.

DISCUSSION

These data show that metabolic stressors cause early and progressive CI, with inflammatory changes that promote disease. They also indicate a role for microglia, particularly microglial SPP1, in CI.

Highlights

Metabolic stress causes persistent metabolic and cognitive impairments in mice.
Murine and human brain spatial transcriptomics align and indicate a pro-inflammatory milieu.
Transcriptomic data indicate a role for microglial-mediated inflammatory mechanisms.
Secreted phosphoprotein 1 emerged as a potential target of interest in metabolically driven cognitive impairment.

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.