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Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis.
J Neurosci. 2014 Jul 16; 34(29):9607-20.JN

Abstract

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.

Authors+Show Affiliations

Department of Neurology and the Hope Center for Neurological Disorders and.Department of Neurology and the Hope Center for Neurological Disorders and.Division of Cardiology and Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110, and John Cochran VA Medical Center, St. Louis, Missouri 63108.Division of Cardiology and Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110, and.Department of Neurology and the Hope Center for Neurological Disorders and.Department of Neurology and the Hope Center for Neurological Disorders and.Department of Neurology and the Hope Center for Neurological Disorders and.Department of Neurology and the Hope Center for Neurological Disorders and.Department of Neurology and the Hope Center for Neurological Disorders and.Department of Neurology and the Hope Center for Neurological Disorders and.Division of Cardiology and Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110, and John Cochran VA Medical Center, St. Louis, Missouri 63108 leejm@wustl.edu adiwan@dom.wustl.edu.Department of Neurology and the Hope Center for Neurological Disorders and leejm@wustl.edu adiwan@dom.wustl.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25031402

Citation

Xiao, Qingli, et al. "Enhancing Astrocytic Lysosome Biogenesis Facilitates Aβ Clearance and Attenuates Amyloid Plaque Pathogenesis." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 34, no. 29, 2014, pp. 9607-20.
Xiao Q, Yan P, Ma X, et al. Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. J Neurosci. 2014;34(29):9607-20.
Xiao, Q., Yan, P., Ma, X., Liu, H., Perez, R., Zhu, A., Gonzales, E., Burchett, J. M., Schuler, D. R., Cirrito, J. R., Diwan, A., & Lee, J. M. (2014). Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 34(29), 9607-20. https://doi.org/10.1523/JNEUROSCI.3788-13.2014
Xiao Q, et al. Enhancing Astrocytic Lysosome Biogenesis Facilitates Aβ Clearance and Attenuates Amyloid Plaque Pathogenesis. J Neurosci. 2014 Jul 16;34(29):9607-20. PubMed PMID: 25031402.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. AU - Xiao,Qingli, AU - Yan,Ping, AU - Ma,Xiucui, AU - Liu,Haiyan, AU - Perez,Ronaldo, AU - Zhu,Alec, AU - Gonzales,Ernesto, AU - Burchett,Jack M, AU - Schuler,Dorothy R, AU - Cirrito,John R, AU - Diwan,Abhinav, AU - Lee,Jin-Moo, PY - 2014/7/18/entrez PY - 2014/7/18/pubmed PY - 2014/9/6/medline KW - Alzheimer's disease KW - TFEB KW - amyloid KW - astrocytes KW - lysosomes SP - 9607 EP - 20 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 34 IS - 29 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/25031402/Enhancing_astrocytic_lysosome_biogenesis_facilitates_Aβ_clearance_and_attenuates_amyloid_plaque_pathogenesis_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=25031402 DB - PRIME DP - Unbound Medicine ER -