HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease.
Overview
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine,Hangzhou, Zhejiang 310003 China
- Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang 310002 China
- Lingang Laboratory, Shanghai, 200120 China
- School of Nursing and Health, Henan Medical College, Zhengzhou University,Zhengzhou, Henan 450001 China
- School of Brain Science and Brain Medicine, Zhejiang University,Hangzhou, Zhejiang 310012 China
- Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine,Hangzhou, Zhejiang, 310003 China
- National Human Brain Bank for Health and Disease, Zhejiang University,Hangzhou, Zhejiang 310012 China
Abstract
Background: Dysregulation of multivesicular bodies (MVBs) in Alzheimer’s disease (AD) contributes to aberrant tau secretion via extracellular vesicles (EVs). This may potentially explain our previous paradoxical observation of elevated free-form p-tau217 alongside reduced p-tau217+ EVs in plasma. This study aimed to investigate the mechanisms underlying the reduction of p-tau217+ EVs to uncover AD therapeutic targets.
Methods: By integrating hippocampal spatial transcriptomics of human brain with EV proteomics of cerebrospinal fluid, we identified key regulators of p-tau217+ EV release. Subsequently, we investigated the mechanisms underlying the synthesis and secretion of p-tau217+ EVs. The regulatory roles of these candidate proteins were systematically evaluated through shRNA knockdown and interference with a synthetic peptide in both Aβ42-treated cells and AD model mice.
Results: Heat shock protein family A member 8 (HSPA8) was identified as a crucial regulator of EV biogenesis and release, mediating the Aβ–SNAP29 interaction to disrupt SNARE complex assembly and impair p-tau217+ EV secretion. In AD models, HSPA8 inhibition with shRNA rescued p-tau217+ EVs and improved cognitive function. Additionally, blocking the Aβ–SNAP29 interaction with a selective peptide inhibitor for HSPA8 reversed the decline in p-tau217+ EV and cognitive deficits.
Conclusions: These findings reveal a role of HSPA8 in regulating the MVB-mediated EV release and tau propagation, and highlight HSPA8 as a promising therapeutic target for modifying AD progression.
Supplementary Information: The online version contains supplementary material available at 10.1186/
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
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search/ , at db.cngb.org; found in “Data availability”project
Data availability
The datasets analysed in the current study are available in the CNGB Nucleotide Sequence Archive (accession code: CNP0005077; https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 5 keywords, 11 MeSH terms, 4 funders, 43 references, 1 RRID.
Cite
This paper
Xu, B., Guo, Z., Chen, J., Xie, Y., Wang, P., Xiong, X., Yu, J., Xu, Z., Fu, Y., Lan, Z., Peng, G., & Zhang, J. (2026). HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease. Translational neurodegeneration, 15(1), 42. https://
BibTeX
@article{xu2026hspa8,
author = {Xu, Bin and Guo, Zhen and Chen, Jun and Xie, Yazhou and Wang, Pan and Xiong, Xiao and Yu, Jiayi and Xu, Zhi and Fu, Yuan and Lan, Zhuoqing and Peng, Guoping and Zhang, Jing},
title = {{HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease}},
journal = {Translational neurodegeneration},
year = {2026},
month = aug,
volume = {15},
number = {1},
pages = {42},
publisher = {BMC},
issn = {2047-9158},
doi = {10.1186/
url = {https://
pmid = {42661225},
pmcid = {PMC13520189}
}
RIS
TY - JOUR
AU - Xu, Bin
AU - Guo, Zhen
AU - Chen, Jun
AU - Xie, Yazhou
AU - Wang, Pan
AU - Xiong, Xiao
AU - Yu, Jiayi
AU - Xu, Zhi
AU - Fu, Yuan
AU - Lan, Zhuoqing
AU - Peng, Guoping
AU - Zhang, Jing
TI - HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease
T2 - Translational neurodegeneration
J2 - Transl Neurodegener
PY - 2026
DA - 2026/
VL - 15
IS - 1
SP - 42
SN - 2047-9158
PB - BMC
DO - 10.1186/
UR - https://
LA - en
ER -
CSL-JSON
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