Enhancing Astrocytic Lysosome Biogenesis Facilitates Aβ Clearance and Attenuates Amyloid Plaque Pathogenesis

Jul 18, 2014The Journal of neuroscience : the official journal of the Society for Neuroscience

Improving brain support cells' waste recycling helps clear amyloid beta and reduces plaque buildup

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Abstract

Enhancement of lysosomal function in astrocytes through transcription factor EB (TFEB) led to reduced Aβ levels and amyloid plaque load in the hippocampus of transgenic mice.

Impaired removal of amyloid-beta (Aβ) is associated with elevated levels contributing to amyloid plaque development in Alzheimer's disease.
Astrocytes are capable of taking up and degrading Aβ, but their efficiency in Alzheimer's disease may be insufficient.
Exogenous TFEB localized to the nucleus and induced lysosomal biogenesis and function, enhancing Aβ uptake and degradation in vitro.
Stereotactic injection of TFEB resulted in astrocyte-specific expression and improved lysosomal function in the hippocampus of APP/PS1 mice.
Enhanced lysosomal function led to significantly reduced Aβ levels and a decrease in amyloid plaque burden in treated mice.

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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.

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Enhancing Astrocytic Lysosome Biogenesis Facilitates Aβ Clearance and Attenuates Amyloid Plaque Pathogenesis

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