Oleic acid improves pathological changes in Aβ1–42-induced astrocytes and Alzheimer’s disease mouse models through PKA/ACACB/CPT1A

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Emerging evidence indicates that fatty acid oxidation is impaired in both patients with AD and AD animal models. In the brain, fatty acid metabolism occurs predominantly in astrocytes. Diets enriched in monounsaturated fatty acids (MUFAs) are often recommended for individuals with AD. Oleic acid (OA), a common dietary MUFA, has been shown to reduce amyloid plaque accumulation in transgenic mouse models of AD. Moreover, OA decreases the expression of acetyl-CoA carboxylase beta (ACACB/ACC2), a key regulator of fatty acid β-oxidation. However, the precise mechanism by which OA may alleviate amyloid plaque deposition through modulation of brain fatty acid metabolism remains unclear. Objective: To determine whether dietary OA supplementation partially restores astrocytic fatty acid metabolism by suppressing ACACB and enhancing fatty acid β-oxidation, thereby attenuating AD-related pathology. Methods: Using NHANES 2011-2014 data, we applied survey-weighted multivariable logistic regression to examine the association between energy-adjusted MUFA intake and low cognitive function, with adjustment for multiple testing. We then screened GEO datasets to identify AD-associated genes involved in fatty acid metabolic dysregulation, identifying ACACB as a candidate target. The expression of ACACB and its downstream effector carnitine palmitoyltransferase 1A (CPT1A) were validated in mouse and cell models. APP/PS1 mice received dietary OA supplementation, followed by behavioral testing and brain histopathological analyses. In parallel, an Aβ1-42-induced astrocyte injury model was used to assess lipid droplet accumulation, mitochondrial function, and cellular energy metabolism. ACACB knockdown/overexpression and CPT1A overexpression were used to test pathway-specific effects of OA. Results: , OA modulated ACC2 activity through protein kinase A (PKA) signaling, increased fatty acid β-oxidation, reduced lipid droplet accumulation, restored mitochondrial membrane potential and ATP production, and enhanced astrocyte-mediated support of neuronal synaptic growth. Conclusion: OA ameliorates AD-related pathology and cognitive impairment by restoring astrocytic fatty acid β-oxidation through the PKA/ACACB/CPT1A pathway.