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Ketone body β-hydroxybutyrate restores Tau proteostasis via metabolism-independent mechanism

ABSTRACT: Alzheimer’s disease (AD) and related tauopathies are marked by brain accumulation of pathological Tau aggregates and associated metabolic dysfunction. Metabolic interventions including ketogenic diets, caloric restriction, and exercise have shown promise in ameliorating cognitive impairments in AD, but variable efficacy and issues of compliance and side effects mar their translational potential. A shared molecular feature between these interventions is the induction of ketosis, a metabolic state marked by elevated circulating levels of β-hydroxybutyrate (βHB). Previous studies show βHB administration directly or in the form of a precursor can reproduce and even improve upon the benefits of metabolic interventions, but the molecular mechanism underlying the neuroprotective properties of βHB in AD remains to be elucidated. In the current study, we find that a βHB precursor diet is sufficient to ameliorate Tau pathophysiology in the PS19 mouse model at both the pathological and single-cell levels. This GEO record is for the hippocampal single nucleus RNA sequencing data generated for our diet paradigm.

ORGANISM(S): Mus musculus

PROVIDER: GSE314609 | GEO | 2026/02/06

REPOSITORIES: GEO

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Project description:Alzheimer'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.

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Ketone body β-hydroxybutyrate restores Tau proteostasis via metabolism-independent mechanism

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