期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 35, 页码 12137-12151出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0705-15.2015
关键词
Alzheimer's disease; amyloid; amyloid precursor protein; lysosome; TFEB
资金
- Alzheimer's Association [NIRG 12-242588]
- Brightfocus Foundation [A2012151]
- National Institutes of Health [R21 NS082529, R01 AG042513, R21 AG045691]
- Fondazione Telethon Funding Source: Custom
In AD, an imbalance between A beta production and removal drives elevated brain A beta levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via alpha-cleavage at the plasma membrane, amyloidogenic beta- and gamma-cleavage within endosomes to generate A beta, 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 beta 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 alpha and beta C-terminal APP fragments (CTFs), and in the steady-state A beta levels in the brain interstitial fluid. In aged mice, total A beta 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 alpha- and beta-CTFs, and attenuated A beta 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 beta generation. Activation of TFEB in neurons is an effective strategy to attenuate A beta generation and attenuate amyloid plaque deposition in AD.
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