# Study of cell-type specific Alzheimer's disease genetic variants using a novel bioengineered model of iPSC-derived neural tissue

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2021 · $975,889

## Abstract

ABSTRACT
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory impairments
and cognitive deterioration. Aging is the major risk factor for AD. Furthermore, increasing evidence indicates
that astrocytes and microglia are implicated in the pathogenesis of AD. The ε4 allele of the apolipoprotein E
gene (APOE) has been identified as a major risk factor contributing to the pathogenesis of sporadic AD (SAD)
in about 15-20% of the cases. APOE is the major apolipoprotein expressed in the human brain primarily by
astrocytes and to a lesser extent by microglia, and is involved in cholesterol homeostasis, and regulates A
clearance. Furthermore, genome-wide association studies (GWAS) have identified polymorphisms in genes
enriched in microglia (e.g. SORL1, CR1, CD2AP, CD33, TREM2, ABCA7) and astrocytes (e.g. CLU and
ABCA7) that increase the risk of developing AD. Recent advances in stem cell technology have allowed the
reprogramming of primary cells from human subjects into induced pluripotent stem cells (iPSCs) and their
differentiation in neurons, astrocytes and microglia. However, conventional 2D culture systems fail to
recapitulate the diversity and maturation of multiple cell types and their interaction under physiological and
pathological conditions. To overcome these weaknesses we have developed a novel bioengineered model of
iPSC-derived neural tissue. Our silk-collagen protein-based ‘donut’ scaffolds can support compartmentalized,
3D brain-like tissues over a year, without necrosis. This tissue model is highly innovative, supporting the
differentiating neurons growth in a donut-shaped porous silk sponge within an optically cleared collagen-filled
central region for axon connectivity and synapse formation, that will allow for the first time live in vivo studies
(e.g., cell-based electrophysiology, trafficking, synaptic functionality) of an human AD brain-like tissue during
ageing (months of cultivation) under controlled experimental conditions. More importantly, the architecture of
the scaffolds was optimized to meet the metabolic demand of high-density cell cultures in terms of free
diffusion of nutrients and oxygen, a fundamental requisite for long-term cultures and ageing-related studies.
Thus, we propose to: 1) Assess genotype-phenotype relationship of AD genetic variants enriched in astrocytes
and microglia in patient-derived 3D brain-like cultures; 2) Assess genotype-phenotype relationship of AD
genetic variants in vivo after transplantation of patient-derived cells in mice.

## Key facts

- **NIH application ID:** 10146265
- **Project number:** 5R01AG061838-02
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** PHILIP G HAYDON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $975,889
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146265

## Citation

> US National Institutes of Health, RePORTER application 10146265, Study of cell-type specific Alzheimer's disease genetic variants using a novel bioengineered model of iPSC-derived neural tissue (5R01AG061838-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146265. Licensed CC0.

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