Neurotoxic Astrocytes and Alzheimer's Disease

PROJECT DESCRIPTION: The goal of this R01 proposal is to investigate a novel molecular mechanism by which extracellular cold-inducible RNA-binding protein (eCIRP) induces neurotoxic astrocytes and their critical role in Alzheimer’s disease (AD) pathogenesis. We also plan to evaluate the potential of targeting eCIRP- induced neurotoxic astrocytes as a treatment for AD. AD is the fifth leading cause of death in the US and the most common form of neurodegenerative dementia. Although astrogliosis correlates with neurodegeneration and cognitive decline in AD, solid support for the causative role of neurotoxic astrocytes in AD is still lacking. In our preliminary studies, we found elevated levels of eCIRP in the cerebrospinal fluid and blood of AD patients as well as in hTau.P301S mice, a model of AD tauopathy. Plasma levels of eCIRP in AD patients strongly correlated with glial fibrillary acidic protein, a marker of astrocyte reactivity. Indeed, eCIRP induced neurotoxic astrocytes and their release of proinflammatory and neurotoxic factors, both in vitro and in vivo. We showed that eCIRP binds with high affinity to triggering receptor expressed on myeloid cells-1 (TREM-1), and that both astrocytes from TREM-1 knockout mice and wild type astrocytes pretreated with the TREM-1 selective inhibitor LP17 were resistant to eCIRP induction of neurotoxic astrocytes. Moreover, astrocytes exposed to eCIRP had higher total and surface TREM-1 protein levels, increased Syk phosphorylation, and upregulated NFB mRNA expression. Therefore, we hypothesize that neurotoxic astrocytes induced by eCIRP via TREM-1 play a critical role in AD pathogenesis. We designed M3, a small anti-eCIRP peptide, and demonstrated that M3 abolishes eCIRP’s induction of neurotoxic astrocytes both in vitro and in vivo, and crosses the blood-brain barrier. As such, we further hypothesize that treatment with M3 attenuates neurotoxic astrocyte-associated cognitive deficit in AD. Thus, in this project, we will further establish the critical role of eCIRP-induced neurotoxic astrocytes in AD pathogenesis, elucidate the mechanisms responsible for the induction and neurotoxicity of eCIRP-induced neurotoxic astrocytes, and determine the therapeutic potential of targeting eCIRP-induced neurotoxic astrocytes to improve cognition in AD. These studies shall provide novel pivotal insights into the induction, role, and effector mechanisms of neurotoxic astrocytes in AD pathogenesis, as well as a new potential therapeutic strategy to treat AD patients in future. Project Number: 1RF1AG091371-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Archna Sharma (+2 co-PIs) | Institution: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, MANHASSET, NY | Award Amount: $2,557,950 | Activity Code: RF1 | Study Section: Special Emphasis Panel[ZRG1 AN-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11229493