TFEB Activation to Restore Lysosomal Biogenesis in Aged Synapses

TFEB (together with TFE3 and TFEB family members) is a master transcriptional regulator of lysosomal biogenesis and autophagy. In aged synapses, lysosomal degradation is often impaired, a defect reflected by autophagosome accumulation despite intact initiation (PMID 30401736). In Alzheimer’s disease (AD) brain tissue, mTOR hyperactivation prevents TFEB nuclear translocation, limiting lysosomal gene expression (PMID 29079772). Pharmacologic inhibition of mTOR with rapamycin analogs or direct overexpression of TFEB can promote nuclear TFEB localization and has been shown to reduce tau aggregation and Aβ toxicity in cellular models (PMID 25661182). Moreover, TFEB activation can bypass upstream mTOR dysregulation and directly drive expression of lysosomal hydrolases and membrane proteins (PMID 31835980). However, TFEB governs a broad transcriptional network that includes lipid metabolism and inflammatory pathways (PMID 28628114), and global or neuron‑non‑specific overexpression can exacerbate neurodegeneration in α‑synuclein models via APP‑like substrate processing (PMID 31225475). Microglial activation resulting from global TFEB activity also heightens neuroinflammation through enhanced lysosomal antigen presentation (PMID 33004405). Interestingly, TFEB haploinsufficiency exhibits protective effects in some aging paradigms, suggesting a “Goldilocks” principle where an optimal level of TFEB activity is required (PMID 30459173). Complementary strategies such as trehalose, a chemical chaperone that promotes lysosomal biogenesis independently of TFEB (PMID 25205291, 28628114), may provide additive benefits without the pleiotropic effects of direct TFEB activation. Thus, a targeted, cell‑type‑specific modulation of TFEB activity at a precise level—potentially combined with trehalose—could restore lysosomal function in aged synapses, but must carefully balance the risk of off‑target gene expression and inflammatory responses. Further studies are needed to define the optimal window of TFEB activation and to evaluate the long‑term consequences in human neurons.