# Regulation of gamma-secretase function in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $386,752

## Abstract

7. PROJECT SUMMARY
Alzheimer's disease (AD) is one of the most significant medical and societal challenges of our time and yet no
current intervention strategies can halt or modify the underlying disease course. By attaining a more thorough
understanding of the cellular processes that underlie disease pathogenesis, and by linking molecular and
biochemical changes to specific clinical manifestations of the disease, we believe that efficacious, mechanism-
based therapeutic strategies can be developed. Neuropathologically, the AD brain is characterized by the
accumulation of aggregates of the amyloid-β (Aβ) peptide and neurofibrillary tangles (NFTs) composed of the
hyperphosphorylated microtubule-associated protein tau. Importantly, several studies have revealed an
important link between Aβ and tau pathology. Aβ is derived from proteolysis of the β-amyloid precursor protein
(APP) following sequential cleavage by the β- and γ-secretases. G protein-coupled receptors (GPCRs) are
involved in key neurotransmitter systems that are disrupted in AD patients and are also associated with
multiple stages of APP proteolysis, indicating an intimate association between GPCRs and the molecular
pathways involved in AD. However, the true molecular nature of these relationships remains only partially
understood. We have identified the orphan GPCR GPR3 as a key modulator of γ-secretase activity and
determined that β-arrestin 2 (βarr2), which belongs to a small family of multifunctional GPCR adaptor proteins,
specifically interacts with the γ-secretase complex and, critically, is required for the GPR3-mediated effect on
Aβ generation. These results support the hypothesis that βarr2 may be a critical link between GPCR
dysfunction and the γ-secretase complex in AD. We propose three multidisciplinary Aims to comprehensively
investigate the mechanism through which GPR3 and βarr2 cooperate to regulate γ-secretase function. Aim 1
will focus on determination of mechanism through which GPR3 and βarr2 regulate of the activity, substrate
selectivity, and heterogeneity of the γ-secretase complex. Aim 2 will focus on determination of the in vivo
consequence of selective abrogation of βarr2-dependent signaling on γ-secretase function, which is likely
essential for triggering physiological and pathophysiological outcomes in mouse models of the disease. Aim 3
will focus on elucidation of the pathophysiological role that the GPCR kinases (GRKs) play in βarr2 recruitment
to GPR3, GPR3 phosphorylation, and/or modulation of γ-secretase function. The proposed studies will provide
the first demonstration of the in vivo consequence of selective modulation of βarr2-dependent signaling in AD
pathogenesis and investigate the previously unappreciated role of GRKs in modulation of γ-secretase function.
Results from these studies will not only address a major challenge in understanding disease mechanisms in
AD, they will also provide new avenues for the development of potential therapeutic target...

## Key facts

- **NIH application ID:** 9851310
- **Project number:** 5R01AG058851-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Amantha Thathiah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,752
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851310

## Citation

> US National Institutes of Health, RePORTER application 9851310, Regulation of gamma-secretase function in Alzheimer's disease (5R01AG058851-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851310. Licensed CC0.

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