# Functional dissection of fibronectin type 3 domains of SORL1 in Alzheimers disease associated microglia

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $485,688

## Abstract

Functional dissection of fibronectin type 3 domains of SORL1 in Alzheimer's
 disease associated microglia
Alzheimer's disease (AD) is a multifactorial, complex disease and a leading cause of dementia
among aged people. There are no effective pharmacotherapeutic options for prevention and
treatment of AD due to lack of complete understanding of disease mechanisms. Interestingly,
Genome wide association studies have established that the majority of AD associated loci are
found in or near genes that are highly/uniquely expressed in microglia (resident macrophage cells
of brain) suggesting the critical role of these cells in disease progression. SORL1 is genetically
implicated in late and early onset forms of AD. Studies on postmortem brain tissues have shown
reduced levels of SORL1 in AD patient brains. Although, among brain cells microglia show
highest expression of SORL1, yet little is known how this protein regulates microglia phenotypes
during health and disease. Our preliminary data suggest, that a specific isoform of SORL1 is
enriched in microglia and it physically interact through its FN3 domain with WAVE regulator
complex (WRC). WRC is emerging as critical regulator of cell migration and phagocytic response
hence can serve as therapeutic target for tuning up phenotypes of AD related microglia. In this
application, we propose to: (1) determine the molecular mechanism by which SORL1 regulate
microglia functions e.g. phagocytosis, chemotaxis, and cytokine expression; (2) Measure SORL-
FN3 abundance in AD and non-AD brain microglia from cohorts of deeply characterized
individuals (ROSMAP) to establish the relationship among FN3 abundance vs. AD related traits;
(3) Identify therapeutic targets within SORL1-WRC using our newly developed CRISPR-mediated
saturating mutagenesis approach.
Overall, by leveraging innovative CRISPR-Cas9 genome editing technologies (1 & 3) and novel
SRM (selected reaction monitoring) based quantitative proteomics and genetics (2) this proposal
will accelerate the transition of genetic discoveries to molecular mechanism that can open new
avenues for novel therapeutics for AD.

## Key facts

- **NIH application ID:** 10364609
- **Project number:** 5R01AG070118-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Falak Sher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $485,688
- **Award type:** 5
- **Project period:** 2021-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364609

## Citation

> US National Institutes of Health, RePORTER application 10364609, Functional dissection of fibronectin type 3 domains of SORL1 in Alzheimers disease associated microglia (5R01AG070118-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10364609. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*