Reactive astrocytes secrete the chaperone HSPB1 to mediate neuroprotection
Open accessAbstract
Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques and intracellular tau neurofibrillary tangles in Alzheimer’s disease (AD). In addition, AD is characterized by an increase in astrocyte reactivity. The chaperone HSPB1 has been proposed as a marker for reactive astrocytes; however, its astrocytic functions in neurodegeneration remain to be elucidated. Here, we identify that HSPB1 is secreted from astrocytes to exert non–cell-autonomous protective functions. We show that in human AD brain, HSPB1 levels increase in astrocytes that cluster around amyloid plaques, as well as in the adjacent extracellular space. Moreover, in conditions that mimic an inflammatory reactive response, astrocytes increase HSPB1 secretion. Concomitantly, astrocytes and neurons can uptake astrocyte-secreted HSPB1, which is accompanied by an attenuation of the inflammatory response in reactive astrocytes and reduced pathological tau inclusions. Our findings highlight a protective mechanism in disease conditions that encompasses the secretion of a chaperone typically regarded as intracellular.
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HSPB1 is a key stress response protein and reactive astrocyte marker that is secreted proximal to amyloid plaques where it exerts non-cell-autonomous neuroprotection through stabilization of proteostasis.
“Of particular interest was the prominent enrichment of HSPB1, a key stress response protein and reactive astrocyte marker that has recently been shown to be secreted proximal to amyloid plaques where it exerts non-cell-autonomous neuroprotection through the stabilization of proteostasis (60).”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [60]
The Results report increased extracellular HSPB1 near plaque-associated astrocytes and non-cell-autonomous protection against neuronal injury and tau aggregation. The Discussion proposes that HSPB1 may help maintain neuronal proteostasis, but says its downstream mechanism remains an open question; the claim presents proteostasis stabilization as an established mechanism. (LLM, conf=0.84)
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Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aβ
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Self-citationSerum levels of heat shock protein 27 in patients with acute ischemic stroke
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TMT proteomics analysis of cerebrospinal fluid from patients with cerebral venous sinus thrombosis
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Small Heat Shock Proteins: Protein Aggregation Amelioration and Neuro- and Age-Protective Roles
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Characterization and chemoproteomic profiling of protein O-GlcNAcylation in SOD1-G93A mouse model
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Astrocyte–Neuron Interactions in Alzheimer’s Disease
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Clickable immune-microenvironment modulated hydrogels for spinal cord injury repair
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Role of heat shock protein in radiation-induced effect and related potential clinical application
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Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules
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Self-citationHSPB1 alleviates acute-on-chronic liver failure via the P53/Bax pathway
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Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis
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Profiling Protein Aggregate Size Using Single-Molecule Array Technology
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Self-citationInnate immune signaling and functions in astrocytes
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Combating ageing beyond the cell: Emerging roles of extracellular proteostasis
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AI-based characterization of Alzheimer’s disease phenotypes from population-scale single-cell data
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The Role of Astrocytes in the Inflammatory Response in Neurodiseases
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- Authors
- Yang, F., Beltran-Lobo, P., Sung, K., Goldrick, C., Croft, C. L., Nishimura, A., Hedges, E., Mahiddine, F., Troakes, C., Golde, T. E., Perez-Nievas, B. G., Hanger, D. P., Noble, W., & Jimenez-Sanchez, M.
- Affiliations
- King's College London (GB)
- Queen Mary University of London (GB)
- Emory University (US)
- Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe Road, London SE5 9RX, UK.
- ORCID
- Venue
- Science Advances
- Published
- 2024-03-22
- Volume
- 10
- Issue
- 12
- Pages
- eadk9884-eadk9884
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC10954207
- OpenAlex
- W4392982799
- Cited by
- 46
- References
- 95
- Citations by year
- 2026: 21 · 2025: 19 · 2024: 6
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Science Advances (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Funders
- King's College London
- Medical Research Council (MR/V036947/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- HSPB1, reactive astrocytes, neuroprotection, Alzheimer's disease, amyloid plaques, neurofibrillary tangles, molecular chaperones, neuroinflammation, intercellular protein transfer, protein misfolding
- MeSH terms
- Neuroprotection, Alzheimer Disease, Astrocytes, Heat-Shock Proteins, Humans, Amyloid beta-Peptides, tau Proteins, Molecular Chaperones, Plaque, Amyloid
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