TFEB Activation to Restore Lysosomal Biogenesis in Alzheimer's Disease Neuronal Networks

Age-related decline in lysosomal function contributes to the accumulation of pathological protein aggregates in Alzheimer’s disease, particularly amyloid-beta plaques and tau tangles that disrupt synaptic transmission and neuronal survival. This hypothesis proposes that pharmacological or genetic activation of TFEB (Transcription Factor EB) can restore lysosomal biogenesis and autophagy flux specifically in Alzheimer’s disease-affected brain regions. TFEB, a master regulator of the autophagy-lysosomal pathway, becomes sequestered in the cytoplasm during aging and neurodegeneration, reducing its nuclear translocation and transcriptional activity. By enhancing TFEB nuclear localization through mTORC1 inhibition, trehalose treatment, or direct TFEB overexpression, we can upregulate expression of lysosomal genes including LAMP1, cathepsins, and V-ATPase subunits. This enhanced lysosomal capacity will improve clearance of aggregated amyloid-beta oligomers and hyperphosphorylated tau from synaptic terminals and neuronal soma. The intervention is expected to be most effective in early-stage Alzheimer’s disease before extensive neuronal loss occurs. Evidence will be gathered through longitudinal analysis of APP/PS1 and 3xTg-AD mouse models treated with TFEB activators, measuring synaptic protein levels, electrophysiological function, and cognitive performance. Biomarker studies will track lysosomal enzyme activity in cerebrospinal fluid and assess changes in brain amyloid and tau burden using PET imaging. This targeted approach addresses the fundamental cellular waste management deficits underlying Alzheimer’s pathogenesis.