CBD AS A TISSUE- AND TIME-DEPENDENT MODULATOR OF AUTOPHAGY IN DROSOPHILA MELANOGASTER MODEL OF TAU NEUROTOXICITY

Tauopathies feature neurotoxic tau accumulation and altered autophagy; CBD reportedly induces autophagy in cell models. In N2a cells and Drosophila, we assessed cannabinoid effects on autophagy and tau neurodegeneration. Screening four cannabinoids identified CBD as the most consistent inducer, the others inhibitory or inactive; CBD was selected. In larval fat body (mCherry-Atg8a; starvation control; inert ethanol vehicle), acute CBD had no effect, whereas chronic treatment significantly increased Atg8a foci without changing Ref(2)P, indicating induced flux, confirmed with tandem GFP-mCherry-Atg8a. In a validated GMR>hTau rough-eye model, chronic CBD did not rescue photoreceptor disorganization; higher doses are under test for dose-limiting effects, and the assay may miss mild effects, warranting complementary approaches. Reanalysing public brain RNA-seq/proteomics (TauWT vs TauR406W across aging), only TauR406W significantly dysregulated autophagy genes and proteins, mainly post-transcriptionally and independently of the age-related decline across genotypes; the null TauWT result may reflect timing, as WT tau phenotypes emerge later. Since CBD boosts flux in vivo, it may counteract tau-driven pathway dysfunction; we are testing this: western blot of total and phospho-tau (pS214, pS396) in adult brains is validated, imaging under way. Together, CBD is a tissue- and time-dependent autophagy modulator, providing new in vivo tools to dissect its role in tau neurodegeneration.