# Investigating a positive biological role for the A Beta peptide

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $202,500

## Abstract

Abstract
 Despite a century of research and countless clinical trials, Alzheimer's Disease (AD) etiology is still poorly
understood and treatment options are incredibly limited. The histopathology of the disorder, has generally
focused on the accumulation of neurotoxic plaques in the brain which are composed of the Aβ peptide, a
cleavage product of the Amyloid Precursor Protein (APP). This peptide has received much attention in the AD
field due to its role in Familial Alzheimer's Disease (FAD), a genetic form of the disease with rapid but similar
disease progression. Importantly, FAD is caused by the autosomal dominant inheritance of mutations, in APP
and the presenilin genes. This is significant because presenilin is the catalytic component of the γ-secretase
complex that cleaves APP, releasing Aβ.
 Since anti-amyloidogenic and anti-γ-secretase agents have been largely ineffective in treating AD, and
often even seem to worsen the condition in AD patients, alternative mechanisms need to be considered. One
such mechanism is altered insulin signaling. There are significant links between AD and Type II diabetes
(T2D), and signs of altered insulin resistance have been identified in the brains of AD patients. This is
important as insulin signaling also plays a role in memory formation.
 We believe that these two distinct areas of AD research may actually be closely linked. We believe that it is
irrefutable that Aβ plays a pivotal role in AD pathogenesis, however we also believe that this role has not been
fully illustrated. It has been suggested in select publications that Aβ competes with insulin for binding to both
the insulin receptor and the insulin degrading enzyme. We believe that this activity is responsible for regulating
insulin signaling in the brain. When Aβ levels are altered, insulin signaling may proceed unregulated resulting
in brain insulin resistance with age, as occurs in the periphery of T2D patients.
 Our hypothesis is that Aβ plays a positive biological role in insulin signaling regulation, and that this
regulation is altered in AD. To test this hypothesis, we will generate animal models that expresses both Aβ and
insulin at physiologically accurate levels. In Aim 1, we propose to use the newly developed CRISPR
technology to generate a physiologically relevant fly model of FAD. In Aim 2, we will use in vitro techniques to
test the concept that Aβ and insulin work in tandem to modulate insulin signaling levels. Finally, in Aim 3, we
will use the new FAD fly model to determine if Aβ is required in the brain to regulate insulin signaling, and if this
balance is altered in AD. Upon conclusion of the experiments proposed, we will have determined if Aβ plays a
positive biological role in the regulation of insulin signaling, and if alterations in this regulatory role may
contribute to AD pathogenesis. Further, we will have developed a new, physiologically accurate fly model of
AD which will be an invaluable tool in both our future studie...

## Key facts

- **NIH application ID:** 9971447
- **Project number:** 5R21AG064618-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** THOMAS A JONGENS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,500
- **Award type:** 5
- **Project period:** 2019-07-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971447

## Citation

> US National Institutes of Health, RePORTER application 9971447, Investigating a positive biological role for the A Beta peptide (5R21AG064618-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971447. Licensed CC0.

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