期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 29, 页码 9607-9620出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3788-13.2014
关键词
Alzheimer's disease; amyloid; astrocytes; lysosomes; TFEB
资金
- Alzheimer's Association [NIRG 12-242588]
- Brightfocus Foundation [A2012151]
- National Institutes of Health [R21 NS082529, R01 AG042513]
In sporadic Alzheimer's disease (AD), impaired A beta removal contributes to elevated extracellular A beta levels that drive amyloid plaque pathogenesis. Extracellular proteolysis, export across the blood-brain barrier, and cellular uptake facilitate physiologic A beta clearance. Astrocytes can take up and degrade A beta, but it remains unclear whether this function is insufficient in AD or can be enhanced to accelerate A beta removal. Additionally, age-related dysfunction of lysosomes, the major degradative organelles wherein A beta 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 A beta 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 A beta 42, 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 A beta. 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 A beta 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 A beta removal and counter amyloid plaque pathogenesis in AD.
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