# Pathogenic Role of APP E590D in Alzheimer’s Disease.

> **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $161,000

## Abstract

Project Summary
Our preliminary studies show that the APP E590D variant, identified in two AD patients’ brains, substantially
induces more Aβ than APP-WT in vitro cell line and primary mouse cortical neurons. This APP E590D variant
also significantly increases APP protein stability and APP protein's endocytic process more than APP-WT.
Compared to APP-WT and many other APP mutants, APP E590D generates not only Aβ peptide but also another
extracellular 15kda fragment. Therefore, we take advantage of the human neurons directly converted from
primary fibroblasts to test the hypothesis that APP E590D promotes Aβ pathology while inducing abnormal
endocytosis of APP protein, mitochondrial dysfunction, and impairment of synaptic integrity in human neurons.
Unlike most other classified pathogenic APP missense variants located in the Aβ sequence or C terminus, the
APP E590D variant site is six residues away from the β-cleavage site beyond the Aβ sequence at the N terminus
APP protein, which results in a very conservative protein structure. Considering the patient carrying the APP
E590D variant has not only excessive amyloid deposition but also shows other non-AD-associated
neuropsychological dysfunctions at a very young age, we will (1) identify new C terminal cleavage site of APP
beyond the β-secretase cleavage using a mass spectrometry approach; (2) generate Aβ sequence-humanized
APP E590D knock-in mouse model of AD and test the pathogenic role of APP E590D in vivo.
The successful conclusion of these studies will (1) determine the pathogenic role of APP E590D in human
neurons and mice brains in vivo and uncover a new APP cleavage site with its unique fragment from APP E590D;
(2) provide a new APP E590D-based knock-in animal model of AD for other investigators in the field.

## Key facts

- **NIH application ID:** 10986485
- **Project number:** 1R03AG084948-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Tian Liu
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $161,000
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10986485

## Citation

> US National Institutes of Health, RePORTER application 10986485, Pathogenic Role of APP E590D in Alzheimer’s Disease. (1R03AG084948-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10986485. Licensed CC0.

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