Enhancing Astrocytic Lysosome Biogenesis Facilitates Aβ Clearance and Attenuates Amyloid Plaque Pathogenesis
Open accessAbstract
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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Astrocytes restrict amyloid pathology.
“astrocytes have been shown to restrict amyloid pathology [55–57].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [57]
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Comerota, M. M., Gedam, M., Xiong, W., Jin, F., Deng, L., Wang, M. C., Wang, J., & Zheng, H. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00648-x · Cited by 31 · see citing works
Herzer, S., Hagan, C., von Gerichten, J., Dieterle, V., Munteanu, B., Sandhoff, R., Hopf, C., & Nordström, V. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00206 · Cited by 27 · see citing works
Yu, H., Chen, J., Wang, F., Jia, D., Bi, S., Mao, Y., Zhang, Y., Gao, T., Yang, L., Du, J., et al. (2025) · Advanced Science · doi:10.1002/advs.202502707 · Cited by 14 · see citing works
- Authors
- 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.
- Affiliations
- Hope Center for Neurological Disorders (US)
- Washington University in St. Louis (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-07-16
- Volume
- 34
- Issue
- 29
- Pages
- 9607-9620
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4099542
- OpenAlex
- W2015662447
- Cited by
- 266
- References
- 18
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 21 · 2023: 17 · 2022: 23 · 2021: 36 · 2020: 26 · 2019: 21 · 2018: 25 · 2017: 17 · 2016: 21 · 2015: 17 · 2014: 3
- FWCI
- 12.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- Alzheimer's Association (NIRG-12-242588)
- BrightFocus Foundation (A2012151)
- National Institutes of Health
- National Institute on Aging (R01AG042513)
- National Heart, Lung, and Blood Institute (R01HL107594)
- National Institute of Neurological Disorders and Stroke (R21NS082529)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta clearance, astrocytes, lysosomal biogenesis, TFEB, amyloid plaques, amyloid-beta 42, APP/PS1 mice, glial fibrillary acidic protein promoter, adeno-associated virus vectors, hippocampus, lysosomal dysfunction
- MeSH terms
- Animals, Animals, Newborn, Astrocytes, Cerebral Cortex, Disease Models, Animal, Female, Humans, Lysosomes, Male, Mice, Transgenic, Peptide Fragments, Transfection, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Presenilin-1, Plaque, Amyloid
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