# Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration

> **NIH NIH RF1** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $2,132,716

## Abstract

Abstract
Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disease,
which is largely recognized by the presence of amyloid plaques, neurofibrillary tangles, and
progressive development of neuronal loss. Neuronal loss is an age-associated event, which
exacerbates the loss of synapses and causes severe cognitive dysfunction. Therapeutic
intervention for AD treatment should not only reduce AD pathological hallmarks such as amyloid
deposition and tau aggregation, but also mitigate synaptic impairment and neurodegeneration.
This proposal focuses on pre-clinical therapeutic exploration of C-terminal domain of CX3CL1
(CX3CL1-ICD), which has an activity for inducing neurogenesis and neuroprotection. We have
recently discovered that a CX3CL1-ICD-derived peptide (Tet34) induces activation of insulin
receptor substrate-1 (IRS-1) and IRS-2, and its downstream molecules, Akt and Foxos.
Strikingly, neuronal cells treated with this peptide exhibited significantly reduced cell stress,
cytochrome C release and cleavage of caspase 3, induced by the oligomeric Aβ treatment.
Hence, Tet34 attenuates apoptosis and Aβ-induced cellular toxicity. In this renewal proposal, we
will test the hypothesis that peptides derived from C-terminal CX3CL1 have the translational
potential for improving cognitive functions by decreasing cellular stress, enhancing neural
differentiation and reducing tau-mediated neurodegeneration. Specifically, we will answer the
question of whether N- and C-terminal fragments of CX3CL1 have differential cellular functions,
which potentially antagonize the beneficial effect of CX3CL1 in neurons. We will also explore
the biochemical mechanisms underlying CX3CL1-ICD-dependent neurogenesis in adult and
synaptic regulation. The knowledge gained from this study will allow us to explore our long-term
and ultimate goal, which is to discover more specific molecules that can be used to treat AD
patients. To test our hypothesis, we will employ multiple approaches to address questions in the
following three specific aims: Aim 1: To identify potent short peptides derived from CX3CL1 C-
terminal domain (CX3CL1-ICD) for reducing AD pathology; Aim 2: To determine whether N-
terminal and C-terminal CX3CL1 have differential effects on tau pathology in AD mouse models;
Aim 3: To determine the molecular mechanism underlying CX3CL1-ICD in the control of gene
expression. By accomplishing experiments as proposed, we will gain knowledge that will reveal
the role of CX3CL1-ICD in the control of AD pathogenesis.

## Key facts

- **NIH application ID:** 10594845
- **Project number:** 2RF1AG058261-03
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** RIQIANG YAN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,132,716
- **Award type:** 2
- **Project period:** 2022-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10594845

## Citation

> US National Institutes of Health, RePORTER application 10594845, Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration (2RF1AG058261-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10594845. Licensed CC0.

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