PT  - JOURNAL ARTICLE
AU  - Qingli Xiao
AU  - Ping Yan
AU  - Xiucui Ma
AU  - Haiyan Liu
AU  - Ronaldo Perez
AU  - Alec Zhu
AU  - Ernesto Gonzales
AU  - Jack M. Burchett
AU  - Dorothy R. Schuler
AU  - John R. Cirrito
AU  - Abhinav Diwan
AU  - Jin-Moo Lee
TI  - Enhancing Astrocytic Lysosome Biogenesis Facilitates Aβ Clearance and Attenuates Amyloid Plaque Pathogenesis
AID  - 10.1523/JNEUROSCI.3788-13.2014
DP  - 2014 Jul 16
TA  - The Journal of Neuroscience
PG  - 9607--9620
VI  - 34
IP  - 29
4099  - http://www.jneurosci.org/content/34/29/9607.short
4100  - http://www.jneurosci.org/content/34/29/9607.full
SO  - J. Neurosci.2014 Jul 16; 34
AB  - In sporadic Alzheimer's disease (AD), impaired Aβ removal contributes to elevated extracellular Aβ levels that drive amyloid plaque pathogenesis. Extracellular proteolysis, export across the blood–brain barrier, and cellular uptake facilitate physiologic Aβ clearance. Astrocytes can take up and degrade Aβ, but it remains unclear whether this function is insufficient in AD or can be enhanced to accelerate Aβ removal. Additionally, age-related dysfunction of lysosomes, the major degradative organelles wherein Aβ localizes after uptake, has been implicated in amyloid plaque pathogenesis. We tested the hypothesis that enhancing lysosomal function in astrocytes with transcription factor EB (TFEB), a master regulator of lysosome biogenesis, would promote Aβ uptake and catabolism and attenuate plaque pathogenesis. Exogenous TFEB localized to the nucleus with transcriptional induction of lysosomal biogenesis and function in vitro. This resulted in significantly accelerated uptake of exogenously applied Aβ42, with increased localization to and degradation within lysosomes in C17.2 cells and primary astrocytes, indicating that TFEB is sufficient to coordinately enhance uptake, trafficking, and degradation of Aβ. Stereotactic injection of adeno-associated viral particles carrying TFEB driven by a glial fibrillary acidic protein promoter was used to achieve astrocyte-specific expression in the hippocampus of APP/PS1 transgenic mice. Exogenous TFEB localized to astrocyte nuclei and enhanced lysosome function, resulting in reduced Aβ levels and shortened half-life in the brain interstitial fluid and reduced amyloid plaque load in the hippocampus compared with control virus-injected mice. Therefore, activation of TFEB in astrocytes is an effective strategy to restore adequate Aβ removal and counter amyloid plaque pathogenesis in AD.