# The role of APP in neurogenesis and AD in Down syndrome

> **NIH NIH RF1** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $2,005,131

## Abstract

Down Syndrome (DS) is a genetic disorder caused by the triplication of chromosome 21. DS is
characterized by defective brain development, manifested by intellectual disability. The molecular
mechanisms causing it are not fully understood. Amyloid precursor protein (APP) resides on
chromosome 21, thus triplicated in DS. APP plays a role in developmental and post-natal neurogenesis.
However, studies examining the role of APP overdose on cortical malformation in DS are scarce.
Approximately fifty percent of persons born with DS develop Alzheimer’s Disease (AD) by sixty years
of age. Mutations in APP cause familial AD. Increased dosage of APP is predicted to result in enhanced
accumulation of APP cleavage products including β-amyloid (Aβ). Aggregated Aβ comprises hallmark
amyloid plaques observed in AD brains. Notably, patients with trisomy of chromosome 21 lacking the
APP locus do not develop AD. Thus, it would be important to determine whether an additional copy
of APP is essential or necessary for the development of AD in DS. Our preliminary studies show that
signals critical for neural stem cell proliferation, neuronal differentiation and lamina specification are
reduced in DS organoids. This project will test the hypothesis that APP overexpression causes or
contributes to deficits in neurogenesis and Alzheimer’s pathology in Down Syndrome. We applied
CRISPR-Cas9 technology to eliminate one copy of APP from Down syndrome-derived iPSC [DSAPP].
Using brain organoids developed from DSAPP, DS and isogenic iPSC, experiments in Aim 1 will
examine the role of APP in neural stem cell proliferation and neural lineage commitment in DS, Aim 2
will address the role of APP in neuronal differentiation and cortical organization, and Aim 3 will
examine whether APP overdose in DS is essential or necessary for the development of AD pathology.
These experiments will address critical gaps in understanding DS and AD and identify new therapeutic
targets for these disorders.

## Key facts

- **NIH application ID:** 10519776
- **Project number:** 1RF1AG079002-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Orly Lazarov
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,005,131
- **Award type:** 1
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519776

## Citation

> US National Institutes of Health, RePORTER application 10519776, The role of APP in neurogenesis and AD in Down syndrome (1RF1AG079002-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10519776. Licensed CC0.

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