Study of a novel TFEB activator on attenuating Tau pathology in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting 4–8% of the elderly population worldwide. Currently no drugs are capable of curing this disease. AD is characterized by the deposition of extracellular amyloid plaques composed of β-amyloid peptides (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated Tau protein in the brain. In the past few decades, great efforts have been made for AD drug discovery mainly based on targeting Aβ. However, none of the small molecules used for targeting Aβ have produced meaningful results in clinical trials. Given that hyperphosphorylated Tau in neurofibrillary tangles (NFT) are more strongly correlated with memory deficits than Aβ in clinical research, the target is moving from Aβ to Tau for developing AD drugs. Increasing evidence has demonstrated that activation of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, can ameliorate neurotoxicity and rescue neurodegeneration in AD animal models. However, currently known TFEB activators also inhibit mTOR, a master regulator of cell growth and metabolism. Thus, the identification of TFEB activators, as safe drugs, acting without inhibiting the mTOR pathway would be preferred and would probably have few side effects in AD treatment.

Our group recently screened and identified a synthesized monocarbonyl analog of curcumin, termed C1. C1 binds and activates TFEB to promote autophagy and lysosomal biogenesis in an mTOR-independent manner (Song JX, et al Autophagy 2016). Given the fact that TFEB overexpression promotes the clearance of Tau, we tested the effect of C1 on the degradation of Tau proteins in cells and animal models. Our preliminary data show that C1 promotes the clearance of aberrant Tau in vitro and in vivo. Importantly, C1 improves motor performance in P301S Tau transgenic mice in the Rotarod test. This function improvement is accompanied with significant Tau clearance in Tau transgenic mice. Thus, we hypothesize that C1 activates TFEB to attenuate Tau pathology in AD animal models.

In this study we propose: (1) To consolidate the neuroprotective effects of C1 in P301S Tau transgenic AD mice；(2) To determine the mechanism by which C1 promotes the clearance of aberrant Tau in neuronal cells; and (3) To evaluate the pharmacokinetics and safety of curcumin analog C1. In summary, this study will provide promising pre-clinical data of a novel mTOR-independent, BBB-permeable TFEB activator for developing a disease-modifying drug for AD.