Probing Protein Structural Changes in Alzheimers Disease
Description: PROJECT NARRATIVE Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, affecting more than 5 million Americans and 50 million people worldwide. The development of effective disease-modifying therapeutics for AD would greatly benefit from in vivo biomarkers, preferentially those that tag the very earliest stages of the disease. Despite several existing biomarkers for AD, they do not capture the heterogeneity of the disease and more importantly, lack the sensitivity and specificity for early diagnosis. Given that the accumulation of protein aggredates is a common feature of progressive neurodegenerative diseases, this project aims to develop a novel method that couples limited proteolysis with mass spectrometry to probe system-wide structural changes of proteins in cerebrospinal fluid. By exploring an innovative concept of “conformational biomarkers” and their utility for AD diagnosis and monitoring disease progression, the proposed research offers an exciting opportunity to establish the correlation between conformational biomarkers and conventional pathological features in AD. The folding and unfolding of specific proteins are primary factors driving the disease pathogenesis; therefore, it is revealing to use these functional conformational biomarkers to aid in monitoring pathological progression in AD from asymptomatic preclinical stage to dementia. This will be the first system-wide analysis of protein structure changes in AD. The newly discovered and validated conformational biomarkers would benefit the study of molecular mechanism and facilitate the design of new therapeutic targets in AD. The successful outcome of this research will have broad impact on translational medicine and will have profound impact on the physical and emotional health of millinois of individual patients at risk for this devastating disease.
Funder: National Institute on Aging
Funding type: research
Funder scheme: R21
Start date: 2020-01-15
End date: 2023-12-31
Investigator: LINGJUN LI
Institution: UNIVERSITY OF WISCONSIN-MADISON
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 54
Funder award ID: R21AG065728
OpenAlex ID: G990633214