TY - JOUR T1 - TFEB Overexpression in the P301S Model of Tauopathy Mitigates Increased PHF1 Levels and Lipofuscin Puncta and Rescues Memory deficits JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0042-16.2016 SP - ENEURO.0042-16.2016 AU - Hongjie Wang AU - Ruizhi Wang AU - Ivan Carrera AU - Shaohua Xu AU - Madepalli K. Lakshmana Y1 - 2016/05/11 UR - http://www.eneuro.org/content/early/2016/05/09/ENEURO.0042-16.2016.abstract N2 - Transcription factor, EB (TFEB) was recently shown to be a master regulator of autophagy lysosome pathway (ALP). Here, we successfully generated and characterized transgenic mice overexpressing flag-TFEB. Enhanced autophagy in the flag-TFEB transgenic mice was confirmed by an increase in the cellular autophagy markers both by immunoblots and transmission electron microscopy (TEM). Surprisingly, in the flag-TFEB mice we observed increased activity of senescence-associated β-gal (SA-β gal) by about 66% of neurons in the cortex (p<0.001) and 73% of neurons in the hippocampus (p<0.001). More importantly, flag-TFEB expression remarkably reduced the levels of PHF-tau from 372% in the P301S model of tauopathy to 171% (p<0.001) in the cortex and from 436% to 212% (p<0.001) in the hippocampus. Significantly, reduced levels of NeuN in the cortex (38%, p<0.001) and hippocampus (25%, p<0.05) of P301S mice were almost completely restored to WT levels in the P301S/flag-TFEB double transgenic mice. Also, levels of spinophilin in both the cortex (p<0.001) and hippocampus (p<0.001) were restored almost to WT levels. Most importantly, the age-associated lipofuscin granules, which are generally presumed to be non-degradable, were reduced by 57% (p<0.001) in the cortex and by 55% (p<0.001) in the hippocampus in the double transgenic mice. Finally, TFEB overexpression in the P301S mice markedly reversed learning deficits in terms of spatial memory (Barnes maze) as well as working and reference memories (T maze). These data suggest that overexpression of TFEB can reliably enhance autophagy in vivo, reduce levels of PHF-tau, thereby reverse deposition of lipofuscin granules and memory deficits.Significance Statement: The Transcription factor, EB (TFEB) was recently shown to enhance the entire ALP by upregulating more than 35 genes necessary for lysosome biogenesis and autophagy induction. Surprisingly, we found robustly increased senescent-associated β-gal activity in both the cortex and hippocampus of mice overexpressing flag-TFEB. Interestingly, TFEB expression in the P301S model of tauopathy markedly reduced PHF-tau levels which led to significant restoration of synaptic and neuronal markers as well as learning and memory deficits. More importantly, TFEB expression reduced the accumulation of lipofuscin granules, the first demonstration of its kind in vivo. Thus, activation of TFEB in vivo has therapeutic potential not only for tauopathy but several other neurodegenerative disorders characterized by protein aggregates due to defects in autophagy. ER -