Investigating the Impact of Ketogenic Diet on Cerebellar Gene Expression in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by β-amyloid accumulation, neurofibrillary tangles, and chronic neuroinflammation. Genetic factors contribute to AD pathogenesis, but their roles remain unclear. Ketogenic diets (KDs), high-fat, low-carbohydrate regimens inducing ketosis, may offer neuroprotection by enhancing mitochondrial function and reducing neuroinflammation. Clinical studies suggest KD improves cognitive function in AD patients. The cerebellum, traditionally considered less affected in AD, may benefit from KD’s metabolic effects, potentially contributing to its resilience. We analyzed cerebellar expression of Bdnf, Foxo3, Il-6, Sirt1, Gabra1, and Sst in an AD rat model induced by streptozotocin (STZ) injection. RT-qPCR was performed on cerebellar tissue from three groups: STZ-AD (n=6), therapeutic intervention (n=7), and sham controls (n=5). Bdnf expression was significantly higher in the therapeutic group than in STZ-AD and controls (p <0.0001). Sirt1 was also elevated in the therapeutic group compared to STZ-AD (p = 0.048). Il-6 levels increased in STZ-AD and therapeutic groups but were not statistically significant. Foxo3 was significantly reduced in the therapeutic group (p = 0.0047), while Gabra1 was lower in STZ-AD compared to controls (p = 0.0392). Sst expression was reduced in both STZ-AD and therapeutic groups. Our findings suggest KD may modulate cerebellar gene expression in AD, potentially contributing to neuroprotection. Upregulated Bdnf and Sirt1 align with KD’s neuroprotective effects, while Foxo3, Gabra1, and Sst reductions suggest regulatory effects on neurodegeneration. These findings highlight the cerebellum’s role in AD and warrant further investigation.