# Augmenting AXL and MERTK function to restrain cognitive decline and improve health span in mouse models of Alzheimer's Disease

> **NIH NIH RF1** · YALE UNIVERSITY · 2023 · $2,392,160

## Abstract

PROJECT SUMMARY/ABSTRACT
A watershed moment in decades of research in Alzheimer's disease (AD) is the discovery that targeting certain
molecules in microglial cells can improve a hitherto unknown functional mechanism in these cells, and arrest
cognitive decline. The first in class of microglial molecular targets for AD therapy is TREM2. TREM2 expression
is upregulated in microglia in the AD brain, the microglia changes from a homeostatic state to something known
as damage-associated microglia (DAMs) as defined by transcriptomics, and the loss of TREM2 prevents DAM
transition while accelerating disease progression. Notably, the loss of TREM2 prevents the upregulation of
another microglial molecule - AXL. Whether AXL has a critical effector function in the DAM-mediated thwarting
of cognitive decline remained heretofore unknown. We have discovered that augmenting AXL leads to the arrest
of cognitive decline in a mouse model of AD. There is a potential third player in this axis - MERTK. MERTK has
been implicated by an independent study (Huang et al., Nature Immunology, 2021) in the phagocytic engulfment
of filamentous A[l by microglia and its eventual compaction into harmless dense core plaques. Here we propose
a systematic approach to understand this still nebulous process of microglia-mediated arrest of cognitive decline.
First, we will use mouse genetics to investigate the requirement of sequential involvement of TREM2, followed
by AXL and likely subsequently by MERTK in microglia-mediated arrest of cognitive decline in mouse models of
AD through behavioral tests and electrophysiological assessment of learning and memory. Second, we will
correlate these genetic epistasis-associated functional changes in learning and memory to corresponding
transcriptional state of microglia as assessed by single nucleus RNA sequencing. Our third aim is to evaluate
cellular, subcellular, morphological and neuronal network level brain functional changes, including AD
neuropathological hallmarks such as amyloid plaques and tau phosphorylation, as well as microglial functions
such as phagocytosis and/or plaque barrier formation. We hypothesize that a TREM2, AXL and MERTK triad
functions sequentially to engineer a beneficial microglia state, which in turn counters AD-associated ill-effects
that manifest as cognitive decline. Therefore, augmenting the function of this triad would restrain cognitive
decline and preserve brain health in AD. Our study could lead to the development of multivalent engagement of
microglial molecules TREM2, AXL and MERTK, for novel therapeutics in AD.

## Key facts

- **NIH application ID:** 10662677
- **Project number:** 1RF1AG082190-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sourav Ghosh
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,392,160
- **Award type:** 1
- **Project period:** 2023-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10662677

## Citation

> US National Institutes of Health, RePORTER application 10662677, Augmenting AXL and MERTK function to restrain cognitive decline and improve health span in mouse models of Alzheimer's Disease (1RF1AG082190-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10662677. Licensed CC0.

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