# Identifying targets that lower APP as a therapeutic strategy for Alzheimer's disease

> **NIH NIH F32** · BAYLOR COLLEGE OF MEDICINE · 2021 · $68,562

## Abstract

Project Summary
AD, the most common neurodegenerative disease, is characterized pathologically by extracellular aggregation of
Aβ [a cleavage product of amyloid precursor protein (APP)] and intraneuronal neurofibrillary tangles consisting
of hyperphosphorylated tau. As such, AD belongs to the larger family of neurodegenerative proteopathies, which
includes diseases such as Parkinson's (PD) and polyglutamine diseases such as Huntington's (HD) and
spinocerebellar ataxia type 1 (SCA1). One of the many challenges facing drug development for AD is the lack of
new targets capable of modifying the disease course. Ab is the main target for drugs currently in the pipeline, but
it has not yielded any tangible benefits in clinical trials. The goal of this work is to elucidate the possible
pathogenic role of a lipid pathway which regulates the levels of APP and may contribute to the development of
AD. The idea that the brain is sensitive to the steady-state levels of APP is based on two major lines of evidence.
First, studies of other neurodegenerative proteopathies such as PD and SCA1 have established that elevated levels
of the disease-driving protein are pathogenic. Second, human genetic studies show that individuals carrying an
extra copy of APP (e.g., those with Trisomy 21 or APP locus duplication) develop early-onset AD, but rare cases
of partial trisomy 21(PT21), in which APP is not included in the trisomic segment, show no AD neuropathology.
Because lowering the levels of a disease-driving protein have shown benefits in mouse models of SCA1, it is worth
testing whether lowering abnormally elevated APP levels could prevent Aβ generation and mitigate disease. To
identify novel regulators of APP, the Zoghbi lab performed parallel high-throughput shRNA screens in human
cells and flies. Combined data from both screens identified a number of genes that, when inhibited, lowered full-
length APP levels in a transgenic cell line expressing a fluorescently-labeled APP and mitigated toxicity in flies
overexpressing human APP. These candidates were then further tested for their ability to regulate endogenous
APP levels in human cells and surprisingly, I identified two genes, ACSL3 and SLC27A1, which function in the
same pathway to regulate fatty acid metabolism. To determine if there were additional genes that fell into this
pathway, I went back to the original primary cell-based screen data and uncovered a dozen additional genes
involved in lipid metabolism which are absent in the fly genome and were therefore not previously validated.
Three of these, ACOT8, ACADL, and ACAD10 have now been successfully validated in human cells. The overall
objective of this proposal is to test these five candidates in a human cellular model of AD (Aim 1) and in mouse
models of AD (Aim 2) to determine if full-length APP levels can be lowered, APP processing altered, amyloid
pathology mitigated, and a potential mechanistic link between lipid metabolism and APP uncovered. The
disc...

## Key facts

- **NIH application ID:** 10326784
- **Project number:** 5F32AG064814-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jennifer Leigh Johnson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 5
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326784

## Citation

> US National Institutes of Health, RePORTER application 10326784, Identifying targets that lower APP as a therapeutic strategy for Alzheimer's disease (5F32AG064814-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326784. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*