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

Midlife obesity doubles future Alzheimer's disease (AD) risk. We used a transcriptomic discovery approach in dorsal hippocampus of TgF344-AD and WT rats fed standard chow or a high-fat, high-sugar “Western” diet to examine interactions between obesity and AD during mild cognitive impairment (MCI). AD up-regulated cholesterol synthesis, whereas obesity during AD development additionally dysregulated lipid clearance, mitochondrial genes, and neurotransmission pathways, particularly involvin g norepinephrine. Cell-type deconvolution highlighted inflammatory microglial activation in AD development, with multiple additional cell types dysregulated by comorbid obesity. These findings suggest that obesity exacerbates AD development by increasing lipid pathologies and perturbing noradrenergi c signaling.Created with Biorender.com. 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 (A β), 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 t...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research