# Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions

> **NIH NIH R01** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2020 · $379,383

## Abstract

Project Summary
Aggregation of proteins of known sequence is linked to a variety of neurodegenerative
disorders. Familial mutations in the Amyloid Precursor Protein (APP), from which the amyloid β
(Aβ) protein is derived, have been linked with the early onset of Alzheimer's disease (AD). After
fifteen years of fundamental research using computer simulations guided by experiments to
identify the factors that determine in vitro aggregation of Aβ, the stage is now set to address
questions of utmost relevance to AD. They arise in the context of how heterogeneous
membrane environments, cholesterol, and downstream interactions with cofactors affect the
cleavage of APP, the production of Aβ, and subsequent interactions of Aβ oligomers and
receptors mediating their toxic effects. We are uniquely poised to use computational models to
answer these questions and drive advances in critical areas of AD research.
In this computational and theoretical research proposal, augmented by synergistic experimental
research collaborations, we address fundamental biophysical questions with substantial
practical implications articulated in three specific aims. (1) Developing a quantitative
understanding of how membrane lipid composition and structural heterogeneity impacts the
partitioning of APP and secretases critical to the processing of APP in the genesis Aβ. (2)
Elucidating the crucial role cholesterol plays in determining the extent of amyloidogenic
cleavage in the differential processing of APP. (3) Characterizing at the molecular-level the
conformational transitions and interactions involved in the binding of Aβ monomer and
oligomers to cellular prion protein (PrPC), implicated in a plausible mechanism of Aβ cytotoxicity.
The proposed coordinated studies will lead to a fundamental molecular-level understanding of
the network of interactions that are essential to the biogenesis of Aβ protein and its role as a
pathogenic agent in AD. Through the development of novel computational models and
identification of new concepts, the expected outcomes could change the landscape for the use
of simulations and theory not only in the AD field but also in the general study of membrane-
protein interactions.!

## Key facts

- **NIH application ID:** 9926884
- **Project number:** 5R01GM107703-06
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** John E Straub
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,383
- **Award type:** 5
- **Project period:** 2015-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926884

## Citation

> US National Institutes of Health, RePORTER application 9926884, Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions (5R01GM107703-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926884. Licensed CC0.

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