%0 Journal Article
%T Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing A¦Â Generation and Amyloid Plaque Pathogenesis
%A Abhinav Diwan
%A Alec Zhu
%A Andrea Ballabio
%A Danielle L. Tripoli
%A Ernesto Gonzales
%A Haiyan Liu
%A Jin-Moo Lee
%A John R. Cirrito
%A Leah Czerniewski
%A Ping Yan
%A Qingli Xiao
%A Ronaldo Perez
%A Xiucui Ma
%J The Journal of Neurosience
%D 2015
%R 10.1523/JNEUROSCI.0705-15.2015
%X In AD, an imbalance between A¦Â production and removal drives elevated brain A¦Â levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via ¦Á-cleavage at the plasma membrane, amyloidogenic ¦Â- and ¦Ã-cleavage within endosomes to generate A¦Â, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce A¦Â levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adeno-associated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the ¦Á and ¦Â C-terminal APP fragments (CTFs), and in the steady-state A¦Â levels in the brain interstitial fluid. In aged mice, total A¦Â levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and ¦Á- and ¦Â-CTFs, and attenuated A¦Â generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce A¦Â generation. Activation of TFEB in neurons is an effective strategy to attenuate A¦Â generation and attenuate amyloid plaque deposition in AD.

SIGNIFICANCE STATEMENT A key driver for AD pathogenesis is the net balance between production and clearance of A¦Â, the major component of amyloid plaques. Here we demonstrate that lysosomal degradation of holo-APP influences A¦Â production by limiting the availability of APP for amyloidogenic processing. Using viral gene transfer of transcription factor EB (TFEB), a master regulator of lysosome biogenesis in neurons of APP/PS1 mice, steady-state levels of APP were reduced, resulting in decreased interstitial fluid A¦Â levels and attenuated amyloid deposits. These effects were caused by accelerated lysosomal degradation of endocytosed APP, reflected by reduced APP half-life and steady-state levels in TFEB-expressing cells, with resultant decrease in A¦Â production and release. Additional studies are needed to explore the therapeutic potential of this approach
%U http://www.jneurosci.org/content/35/35/12137