The Feinstein Institute for Medical Research in Manhasset, New York, has received a USD 2.6 million NIH RF1 grant from the National Institute on Aging to investigate how extracellular cold-inducible RNA-binding protein (eCIRP) drives neurotoxic astrocyte activity in Alzheimer's disease and whether blocking that pathway can slow cognitive decline.
The eCIRP-TREM-1 pathway in Alzheimer's disease
The four-year award, running through April 2030, funds a preclinical and translational program led by investigators Archna Sharma, Ping Wang, and Philippe Marambaud. The research centers on a proposed mechanism in which eCIRP, detected at elevated levels in the cerebrospinal fluid and blood of Alzheimer's patients, binds to triggering receptor expressed on myeloid cells-1 (TREM-1) on astrocytes, converting them into a neurotoxic state that releases proinflammatory mediators and drives neuronal loss. Preliminary data from the team showed that plasma eCIRP levels in Alzheimer's patients correlated with glial fibrillary acidic protein, a recognized marker of astrocyte reactivity, providing a potential translational link between the proposed mechanism and measurable disease biology.
The team has also developed M3, a small peptide designed to block eCIRP activity. In preclinical models, M3 abolished eCIRP-induced neurotoxic astrocyte conversion both in vitro and in vivo and was shown to cross the blood-brain barrier, a critical pharmacological requirement for any central nervous system therapeutic candidate. The grant will be used to further characterize the eCIRP-TREM-1 signaling axis, define the downstream effector mechanisms responsible for astrocyte neurotoxicity, and test whether M3 treatment can attenuate neuronal loss and cognitive deficits in established Alzheimer's mouse models including hTau.P301S and 3xTg-AD animals.
Translational context
While astrogliosis has long been associated with neurodegeneration and cognitive decline in Alzheimer's disease, causal evidence linking a specific neurotoxic astrocyte subtype to disease progression has remained limited. This program is designed to address that gap by combining human biospecimen analysis, genetic knockout models, and a candidate therapeutic agent within a single funded project. The use of TREM-1 knockout mice and the selective TREM-1 inhibitor LP17 in preliminary work, which rendered astrocytes resistant to eCIRP-induced neurotoxicity, provides mechanistic support for the pathway's functional relevance. The grant will extend those findings using patient-derived induced pluripotent stem cell models alongside the animal work, adding a human cellular dimension to the translational evidence base.