title: Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis.
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.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: Qingli
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Xiucui
authors.initials: X
authors.lastname: Ma
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110, and.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Perez
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: Alec
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Gonzales
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: Jack M
authors.initials: JM
authors.lastname: Burchett
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: Dorothy R
authors.initials: DR
authors.lastname: Schuler
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and.
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.affiliation: 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.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders and leejm@wustl.edu adiwan@dom.wustl.edu.
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C484068:Tcfeb protein, mouse; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; TFEB; amyloid; astrocytes; lysosomes