Extracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer's disease
- 1Feinstein Institutes for Medical Research
Abstract
Extracellular cold-inducible RNA-binding protein (eCIRP) is a crucial neuroinflammatory mediator in ischemic stroke and alcohol-induced memory impairment. We have recently discovered that amyloid{beta} causes microglia to release eCIRP, prompting us to investigate its role in Alzheimer's disease (AD). We found that eCIRP levels were significantly elevated in the cerebrospinal fluid (CSF) and plasma of AD patients compared with age-matched non-AD subjects, as well as in hTau.P301S mice (a model of AD tauopathy) compared with wildtype control mice. Plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients. eCIRP induced neurotoxic astrocyte-specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8-D1a cells, primary murine astrocytes and intracerebroventricular eCIRP-injected C57BL/6 mice brains. In particular, eCIRP increased Complement 3, an astrocytic marker involved in neuroinflammation-associated neurodegeneration. Primary astrocytes from TREM-1 knockout mice were resistant to eCIRP induction of neurotoxic astrocytes. eCIRP increased TREM-1 expression and activation in astrocytes. Blocking CIRP/TREM-1 interaction using peptide M3, effectively attenuated eCIRP's induction of neurotoxic astrocytes. Thus, eCIRP strongly correlates with astrocyte reactivity in AD patients, and eCIRP induces neurotoxic astrocytes via TREM-1, which is attenuated by M3, suggesting a novel therapeutic opportunity to target neurotoxic astrocytes in AD.
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BibTeX
@misc{sharma2026extracellular,
title = {{Extracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer's disease}},
author = {A. Sharma and D. Aylar and D. Lapin and P. Marambaud and P. Wang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752724},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752724v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Extracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer's disease
AU - A. Sharma
AU - D. Aylar
AU - D. Lapin
AU - P. Marambaud
AU - P. Wang
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752724
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752724v1
AB - Extracellular cold-inducible RNA-binding protein (eCIRP) is a crucial neuroinflammatory mediator in ischemic stroke and alcohol-induced memory impairment. We have recently discovered that amyloid{beta} causes microglia to release eCIRP, prompting us to investigate its role in Alzheimer's disease (AD). We found that eCIRP levels were significantly elevated in the cerebrospinal fluid (CSF) and plasma of AD patients compared with age-matched non-AD subjects, as well as in hTau.P301S mice (a model of AD tauopathy) compared with wildtype control mice. Plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients. eCIRP induced neurotoxic astrocyte-specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8-D1a cells, primary murine astrocytes and intracerebroventricular eCIRP-injected C57BL/6 mice brains. In particular, eCIRP increased Complement 3, an astrocytic marker involved in neuroinflammation-associated neurodegeneration. Primary astrocytes from TREM-1 knockout mice were resistant to eCIRP induction of neurotoxic astrocytes. eCIRP increased TREM-1 expression and activation in astrocytes. Blocking CIRP/TREM-1 interaction using peptide M3, effectively attenuated eCIRP's induction of neurotoxic astrocytes. Thus, eCIRP strongly correlates with astrocyte reactivity in AD patients, and eCIRP induces neurotoxic astrocytes via TREM-1, which is attenuated by M3, suggesting a novel therapeutic opportunity to target neurotoxic astrocytes in AD.
ER -