Novel biomarkers and mechanisms of Alzheimer's disease

About This Grant

Project Summary / Abstract Alzheimer's disease (AD) is a devastating dementia with enormous societal burden. Despite recent advances in the development of AD biomarkers and anti-A antibodies as disease-targeting therapies, AD remains challenging to treat, highlighting the urgent need for new biomarkers and targets to improve AD diagnosis and treatment. The goal of this project is to perform innovative research to discover glycosylation-based disease processes and identify glyco-biomarkers and targets for improving AD diagnosis, prognosis, and intervention. Glycosylation is the most prevalent and complex form of protein modification which produces a wide variety of glycosylated proteoforms or glycoforms to control many biological processes, including synaptic function and brain homeostasis. The prevalent localization of glycoproteins and glycoforms in extracellular space and cell surface makes them an attractive source of disease biomarkers and drug targets. Recent evidence obtained by our group and others indicates a link between altered protein glycosylation and AD pathogenesis. However, current knowledge of system-wide changes in protein glycoforms and glycan modifications in AD is limited, and the potential impact of aberrant glycosylation on the etiology of AD and biomarker discovery remain underexplored. The proposed project will address the gap in knowledge and test the novel hypothesis that glycoproteostasis dysregulation and glycoform alterations are critically involved in AD development and progression. We have recently established an innovative platform that integrates intact glycopeptide-based quantitative glycoproteomics and systems biology for large-scale, in-depth analysis of protein glycoforms and site-specific glycan modifications in human patient specimens. We will perform experiments using this transformative platform to elucidate brain glycoproteome alterations in AD and uncover disease-associated targets, networks, and pathways. In addition, we will perform proteome-wide glycoform profiling studies of cerebrospinal fluid and blood specimens from AD and control cases to identify glyco-biomarkers reflective of diverse AD pathophysiology at different disease stages for timely diagnosis and monitoring disease progression. Successful completion of the proposed research will generate new insights into AD pathogenic mechanisms, provide novel biomarkers for AD diagnosis and prognosis, and pave the way forward for developing glycosylation-based therapies to combat this devastating disease.