Because of the recent failures in the development of anti-amyloid therapeutic strategies for curing Alzheimer's disease (AD), it is prompt to re-evaluate the existing amyloid cascade hypothesis from all possible aspects. Among all these efforts, biophysical and structural characterizations of ?-amyloid aggregates in in- vitro model systems, especially the works that involve the high-resolution solid-state nuclear magnetic resonance (ssNMR) spectroscopy, provide invaluable information from the fundamental sides. However so far, most of these high-resolution works have been focused on the atomic structures of either amyloid fibrils or non- fibrillar aggregates. Very little high-resolution studies have been performed to directly probe the cellular membrane disruption effects induced by the aggregation process of ?-amyloid peptides, which are potentially associated with the neurotoxicity mechanisms of the ?-amyloid aggregates. A major challenge that prevented the high-resolution studies of ?-amyloid-peptide-induced membrane disruption effects in model systems was the heterogeneity, which usually involved co-existence of multiple membrane disruption pathways with mixed intermediate structures. This proposal attempts to solve this problem by generating model systems with distinct predominant membrane disruption effects. These model systems, which contain different ? amyloid aggregates and phospholipid liposomes, are characterized by distinct time-dependent membrane disruption features and structurally homogeneous endpoints. Therefore, they can be studied individually in terms of their membrane disruption effects using high-resolution ssNMR approaches. The outcomes of this proposal, if successful, will provide crucial insights on the high-resolution molecular interactions between ? amyloid aggregates and membranes that are responsible to the membrane disruption. These information help to explain the neuronal cellular toxicity of ?-amyloid aggregates, which further contribute to the re-evaluation of amyloid cascade hypothesis.

Public Health Relevance

This project focuses on the high-resolution studies of molecular interactions between ?-amyloid aggregates and membranes that lead to membrane disruptions. The outcomes will shed lights on the neurotoxicity mechanisms of ?-amyloid peptides, and their pathological roles in Alzheimer's diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM125853-04
Application #
10073520
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Wu, Mary Ann
Project Start
2018-01-01
Project End
2022-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
State University of NY, Binghamton
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
090189965
City
Binghamton
State
NY
Country
United States
Zip Code
13902