TY - JOUR
T1 - Reactive astrocytes secrete the chaperone HSPB1 to mediate neuroprotection
AU - Yang, Fangjia
AU - Beltran-Lobo, Paula
AU - Sung, Katherine
AU - Goldrick, Caoimhe
AU - Croft, Cara L
AU - Nishimura, Agnes
AU - Hedges, Erin
AU - Mahiddine, Farah
AU - Troakes, Claire
AU - Golde, Todd E
AU - Perez-Nievas, Beatriz G
AU - Hanger, Diane P
AU - Noble, Wendy
AU - Jimenez-Sanchez, Maria
N1 - Funding Information:
Acknowledgments: We thank G. chennell at the Wohl cellular imaging centre at King\u2019s college london for technical support. PhF-1 and Mc1 antibodies were a gift from the late P. davies. illustrations were created with Biorender.com Funding: this work was supported by a Medical Research council career development Award (MR/n022696/1) and transition Support Award (MR/v036947/1) and the John and lucille van Geest charitable trust to M.J.-S. c.l.c. was supported by a Race Against dementia Alzheimer\u2019s Research UK fellowship (ARUK-RAdF2019A-003). Author contributions: F.Y. and P.B.-l. performed most of the experiments, analysis, and interpretation of the data and contributed to study design. K.S., c.G., c.l.c., A.n., e.h., F.M., c.t., t.e.G., B.G.P.-n., d.P.h., W.n., and M.J.-S. performed additional experiments; provided study materials, analysis, and/or interpretation of the data; and/or contributed to study design. M.J.-S. conceptualized the study, obtained funding, supervised the work, and drafted the manuscript. All authors reviewed and approved the final manuscript. Competing interests: the authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
Publisher Copyright:
© 2024 American Association for the Advancement of Science. All rights reserved.
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85188493344&partnerID=8YFLogxK
U2 - 10.1126/sciadv.adk9884
DO - 10.1126/sciadv.adk9884
M3 - Article
C2 - 38507480
SN - 2375-2548
VL - 10
SP - eadk9884
JO - Science Advances
JF - Science Advances
IS - 12
M1 - eadk9884
ER -
