Targeting C99 Mediated Metabolic Disruptions with Ketone Therapy in Alzheimer's Disease

The role of ketone bodies in Alzheimers disease (AD) remains incompletely understood, particularly regarding their influence on amyloid pathology. While beta}hydroxybutyrate (BHB) has been implicated in neuroprotection, direct evidence for its effects on amyloid beta(Abeta) deposition, aggregation, or clearance is lacking. Furthermore, whether BHB acts as a disease modifying factor or merely confers transient metabolic benefits remains unclear. Addressing this gap is crucial for evaluating the therapeutic potential of ketone metabolism in AD. Here, we investigated the impact of ketone bodies on amyloidogenic toxicity using a Drosophila melanogaster model with targeted expression of human amyloid precursor protein (APP), beta secretase 1 (BACE1), Abeta, and the C99 fragment, an essential intermediate in Abeta generation. Surprisingly, we found that Abeta alone elicited minimal neurotoxicity, whereas C99 expression induced pronounced pathological effects, suggesting a critical, underappreciated role of C99 in AD progression. Further analysis revealed that C99 driven toxicity was associated with autophagic and lysosomal dysfunction, leading to impaired protein clearance, oxidative stress, and mitochondrial abnormalities. Using confocal microscopy and lysosomal pH sensitive markers, we demonstrated that BHB treatment restored lysosomal function and alleviated these pathological changes. Protein protein interaction network analysis in C99 expressing Drosophila brains identified protein phosphatase methylesterase 1 (PPME1) activation as a key driver of autophagic impairment, further supported by machine learning predictions. Finally, mathematical similarity analysis of PPI networks suggested that BHB may exert its neuroprotective effects through mTOR inhibition, positioning it as a potential endogenous modulator of AD related pathology.