# The impact of AD-associated genetic variants in 3D human mixed neural-glial models of AD

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $756,000

## Abstract

Title: The impact of AD-associated genetic variants in 3D human mixed neural-glial models of AD
Project summary
A growing number of Alzheimer’s disease (AD)-associated genes are associated with innate immunity and
neuroinflammatory pathways. Network-based integrative analyses of AD-related genes have shown that
microglial gene networks are strongly associated with AD neuropathology (1,5). We have shown that the
protective AD-associated CD33 variant, rs3865444, leads to reduced CD33 expression and lower levels of
Aβ42)(1). Conversely, microglial TREM2 variants, which increase AD risk, reduce microglial clearance of Ab. In
addition to AD-linked functional variants in CD33 and TREM2, our AD whole genome sequencing (WGS) and
whole exome sequencing (WES) datasets from AD families and case-controls, have revealed functional
variants in AD-associated microglial genes linked to innate immunity and neuroinflammation, including CD33,
TREM2, MS4A cluster, ABCA7, ABI3, PLGC2, CR1, and others. To test the impact of microglial genetic
variants on AD pathogenesis on human genetic background, we developed a novel 3D human neuron-
astrocyte-microglia tri-culture AD model using a unique 3D microfluidic system. We demonstrated that human
microglial cells are recruited towards 3D AD (Ab-producing) neuron-astrocyte cultures via microglia-specific
migration channels, in a chemokine-dependent manner, leading to neuroinflammation and neurodegeneration.
Here, we propose to use our extensive collection of AD WGS and WES datasets, together with our 3D human
tri-culture AD model, to evaluate the pathogenic effects of functional variants in AD-associated innate immune
genes linked to neuroinflammation. In Aim 1, we will identify functional genomic variants and enriched gene
networks that are linked to innate immunity and neuroinflammation. We will then examine the pathogenic roles
of microglial AD risk or protective genes and their functional variants in 3D human mixed neural-astrocyte-
microglial models of AD (Aim 2), explore AD pathogenic pathways that are linked to microglial AD risk genes
and their functional variants using integrated multi-omics approaches, and validate selectively blocking these
pathway (Aim 3). The overarching goals of this proposal are to comprehensively assess the pathogenic effects
of functional variants in innate immune AD-risk genes on AD pathogenesis and explore underlying molecular
networks, which will provide novel therapeutic targets for AD patients.

## Key facts

- **NIH application ID:** 10399510
- **Project number:** 5R01AG061891-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Doo Yeon Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $756,000
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399510

## Citation

> US National Institutes of Health, RePORTER application 10399510, The impact of AD-associated genetic variants in 3D human mixed neural-glial models of AD (5R01AG061891-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10399510. Licensed CC0.

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