# Modeling Alzheimer’s disease using directly reprogrammed isogenic neural cells

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $445,140

## Abstract

Project Summary
Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of disability
and death. However, the precise mechanisms underlying AD pathogenesis remains to be elucidated. Although
many transgenic mouse models have been generated for AD research and these models are important for our
understanding of the pathological basis of the disease, none has captured the entire spectrum of the disease
pathology, including considerable neuronal loss. This is likely due to significant species differences between
mouse and human neural cells. Therefore, there is an urgent need to establish human disease modeling
platforms to complement studies in animal models for AD research and drug development.
 Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs (hiPSCs)
have been widely used for disease modeling and drug discovery. However, given the relative immaturity of
cells differentiated from hiPSC, it is challenging to use them to model late-onset diseases, for which cellular
aging is important in disease pathology. Direct reprogramming is an alternative cellular reprogramming
technology, which allows direct conversion of one type of somatic cells, such as fibroblasts, into another type
of somatic cells, such as neurons. It has been shown that direct reprogramming enables generation of human
neurons that possess key elements of cellular aging, because this reprogramming process does not go
through the rejuvenating iPSC stage.
 The objective of this proposal is to develop aging-relevant cellular models of late-onset AD (LOAD), using
direct reprogramming technology in combination with CRISPR/Cas9-mediated gene editing and 3D neural
culture, in order to recapitulate the age-associated phenotypes and uncover novel pathological mechanisms of
LOAD. We propose to establish cellular models of LOAD using both neurons and astrocytes directly
reprogrammed from patient fibroblasts or differentiated from induced neural stem cells (iNSCs) obtained
through direct reprogramming. While the strongest risk factor for AD is aging, the strongest genetic risk factor
of AD is apolipoprotein (apo) E4. We hypothesize that cellular aging and apoE genotype interact with each
other to initiate and/or modulate LOAD pathologies. Accordingly, we propose three complementary aims to test
this hypothesis. Aim 1: To generate isogenic human fibroblast lines with different apoE genotypes as cell
sources for direct reprogramming. Aim 2: To model LOAD using directly reprogrammed human neurons and
astrocytes. Aim 3: To model LOAD using directly reprogrammed NSC-derived neurons and astrocytes. The
outcomes of the proposed studies will likely help to further define the roles of apoE4 in the development of
age-associated AD pathological features, to uncover novel mechanisms for age and apoE4-related AD
pathogenesis, and to design novel therapeutic strategies for AD.

## Key facts

- **NIH application ID:** 9924428
- **Project number:** 5R01AG056305-04
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** YADONG HUANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,140
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924428

## Citation

> US National Institutes of Health, RePORTER application 9924428, Modeling Alzheimer’s disease using directly reprogrammed isogenic neural cells (5R01AG056305-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9924428. Licensed CC0.

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