# Elucidating the role of SORL1 as an APOE receptor in human astrocytes

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $38,810

## Abstract

Project Summary/Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting more than 30 million people
worldwide. It is the most common cause of dementia, and its pathology includes extensive neuronal loss,
accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles. A number of
large scale meta-analyses of genome wide association studies (GWAS) has analyzed polymorphisms in many
human subjects, and identified more than 20 genes associated with AD risk, which can be classified based on
their known functions: cholesterol metabolism, inflammation, and endocytosis. Our lab seeks to utilize induced
pluripotent stem cells (iPSCs) from patients with familial and sporadic AD to understand the cellular mechanisms
underlying AD. My proposed project will investigate the potential convergent mechanisms of APOE and SORL1
function in the brain. Both APOE and SORL1 are AD risk genes, and APOE (ε4) is the strongest genetic risk
factor for AD. Not only is SORL1 a GWAS hit for late onset AD (LOAD), but recent studies identified SORL1
loss-of-function variants in familial AD patients, suggesting that SORL1 can be a potential causal gene for AD.
Here, I will study the function of SORL1 as a receptor for APOE, which can address the potential convergent
mechanism between these genes. I hypothesize that SORL1 will function as an APOE receptor in human
astrocytes and regulate Aβ clearance. In support of this, publicly available RNA-seq data show that SORL1
transcript is highly expressed in astrocytes over other brain cell types. In addition, APOE has a known role in Aβ
clearance, and SORL1 is in the APOE receptor gene family. These findings, however, do not directly examine
the role of SORL1 in regulating Aβ uptake in astrocytes. Here, I will utilize iPSC-derived astrocytes with different
SORL1 and APOE variants to study the ability of SORL1 to function as an APOE receptor and uptake Aβ. In Aim
1, I will generate iPSC-derived astrocytes and determine SORL1 expression, subcellular localization, and ligand
binding characteristics. Then, In Aim 2, I will use iPSC-derived astrocytes generated from individuals with 1)
different APOE isoforms 2) SORL1 knock out (KO), risk SNPs and missense mutations and 3) other AD risk
SNPs. I then will meticulously characterize Aβ generation, uptake and clearance in these astrocytes. Our
preliminary data suggest that SORL1 is highly expressed in human astrocytes, and SORL1 KO in these
astrocytes results in elevated extracellular Aβ levels. Also, I have shown that iPSC-derived astrocytes reduce
extracellular Aβ levels when treated with exogenous Aβ, opening up the possibility/potential for this assay to
examine the Aβ clearance ability of cells from individuals with various genetic backgrounds. In summary, my
proposal will utilize iPSC-derived astrocytes to examine the novel role of SORL1 as an APOE receptor
in astrocytes, and investigate a potential convergent mechanism that...

## Key facts

- **NIH application ID:** 9983410
- **Project number:** 1F31AG063399-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Hyo Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,810
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983410

## Citation

> US National Institutes of Health, RePORTER application 9983410, Elucidating the role of SORL1 as an APOE receptor in human astrocytes (1F31AG063399-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9983410. Licensed CC0.

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