Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Thea Anderson; Sumeet Sharma; Michael A. Kelberman; Christopher Ware; Nanxi Guo; Zhaohui Qin; David Weinshenker; Marise B. Parent

doi:10.1111/jnc.15900

journal article Jun 30, 2023

Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Thea Anderson

Sumeet Sharma Michael A. Kelberman Christopher Ware Nanxi Guo

Zhaohui Qin David Weinshenker

Marise B. Parent

Journal of Neurochemistry Vol. 168 No. 5 pp. 801-821 · Wiley

View at Publisher Save 10.1111/jnc.15900

Abstract

AbstractAlzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late‐life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344‐AD rats that overexpress mutant human amyloid precursor protein and presenilin‐1 and wild‐type (WT) controls to determine whether inducing obesity with a high‐fat/high‐sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up‐regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC‐dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long‐term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD‐induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD‐induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.image

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Details

Published: Jun 30, 2023
Vol/Issue: 168(5)
Pages: 801-821
License: View

Authors

T

Thea Anderson

Neuroscience Institute Georgia State University Atlanta Georgia USA

S

Sumeet Sharma

Department of Psychiatry and Behavioral Sciences Emory University School of Medicine Atlanta Georgia USA

M

Michael A. Kelberman

Department of Human Genetics Emory University School of Medicine Atlanta Georgia USA

C

Christopher Ware

Neuroscience Institute Georgia State University Atlanta Georgia USA

N

Nanxi Guo

Department of Biostatistics and Bioinformatics Emory University Atlanta Georgia USA

Z

Zhaohui Qin

Department of Biostatistics and Bioinformatics Emory University Atlanta Georgia USA

D

David Weinshenker

Department of Human Genetics Emory University School of Medicine Atlanta Georgia USA

M

Marise B. Parent

Neuroscience Institute Georgia State University Atlanta Georgia USA; Department of Psychology Georgia State University Georgia USA

Funding

National Institute of Diabetes and Digestive and Kidney Diseases Award: 3RO1DK114700‐03S1

National Institute of Mental Health Award: R25 MH101079

National Institute on Aging Award: F31AG069502

Georgia State University

Georgia Clinical and Translational Science Alliance Award: UL1TR002378

Cite This Article

Thea Anderson, Sumeet Sharma, Michael A. Kelberman, et al. (2023). Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline. Journal of Neurochemistry, 168(5), 801-821. https://doi.org/10.1111/jnc.15900

Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

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