# A Novel Drosophila Model to Understand the Role of Innate Immunity in Alzheimer's Disease

> **NIH NIH R03** · ILLINOIS STATE UNIVERSITY · 2020 · $147,000

## Abstract

Project Summary
 Alzheimer’s Disease (AD) is a common neurological disease that results in dementia and affects more
than 5.7 million Americans. At a molecular level AD is characterized by the formation of β-amyloid plaques in
the interneuronal space and neurofibrillary tangles within neurons. The formation of β-amyloid plaques arises
due to the aggregation of the amyloid β (Aβ) peptide, and both soluble Aβ peptides and β-amyloid plaques
have been linked to cytotoxicity and AD pathogenesis. Despite these clear links to AD, the normal
physiological role of Aβ is incompletely understood. Recent research suggests that Aβ plays a role in the
innate immune response to infection, and accordingly pathogen infection has been associated with increased
levels of Aβ and the subsequent formation of β-amyloid plaques. The goal of the proposed research is to test
the link between Aβ and innate immune responses using the Drosophila melanogaster-parasitoid wasp model
system. In this system, Drosophila are infected by wasps and mount a genetically conserved cellular innate
immune response to kill the invading parasite. Preliminary studies show that loss the Aβ precursor protein
APPL blocks the production of a successful immune response, suggesting that the role of Aβ in host defense is
evolutionarily conserved. Specific Aim 1 will further define the roles of Aβ, APPL and the APPL processing
enzyme BACE in the innate immune response. Notably, the overexpression of human Aβ in Drosophila leads
to an infection dependent autoimmune response, in which Aβ appears to target immune cells against self
tissue, leading to immune induced tissue damage. Specific Aim 1 will also provide insight into the role of Aβ in
the production of this self directed immune damage, including characterizing the localization of Aβ during the
immune response and identifying the immune cell receptors that are responding to Aβ expression. Additionally,
during infection the parasitoid wasps transfer venom proteins into the Drosophila host. This venom contains
virulence factors that allow the parasite to overcome the host immune response. Two parasitoid wasp species
have been identified that block the self directed immune damage mediated by Aβ expression, suggesting that
they utilize venom virulence proteins that target Aβ. Specific Aim 2 will characterize this activity and identify the
Aβ inhibitory proteins found in parasite venom. This proposal will provide insight into the relationship between
Aβ and innate immunity and may help uncover novel targets for the treatment of AD.

## Key facts

- **NIH application ID:** 9891933
- **Project number:** 5R03AG063314-02
- **Recipient organization:** ILLINOIS STATE UNIVERSITY
- **Principal Investigator:** Nathan Terry Mortimer
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $147,000
- **Award type:** 5
- **Project period:** 2019-03-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891933

## Citation

> US National Institutes of Health, RePORTER application 9891933, A Novel Drosophila Model to Understand the Role of Innate Immunity in Alzheimer's Disease (5R03AG063314-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891933. Licensed CC0.

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