Human neurodegenerative diseases, such as Alzheimer's disease (AD) which is the primary cause of dementia, Creutzfeldt-Jakob disease and Parkinson's disease, are devastating illnesses that predominantly affect elderly people. The hallmark of these diseases are pathogenic oligomers and fibrils of misfolded amyloidogenic proteins (e.g. Aβ and hyper-phosphorylated tau in AD), which cause progressive loss of neurons in the brain and nervous system.
Interestingly, several reports indicated vast deviations from normal protein glycosylation in the brain of AD patients, while others demonstrated alterations in glycosylation of specific proteins related to AD pathology in the disease state, such as tau and APP, the Aβ precursor. Yet, a causal link between alterations in protein glycosylation and AD-related neurodegeneration remains to be demonstrated. This is the goal of our work.
Using an in silico approach we found that many glycosylation-related enzymes exhibit different expression profile in brains of human AD patients as compared with healthy subjects. Utilizing a more direct approach, we experimentally intervene in global protein glycosylation and study the effect of enhancing or reducing expression of the glycosylation-related genes in transgenic Drosophila over-expressing human tau, which serve as an established AD model. We were able to identify leading glycosylation enzymes, both augementing and ameliorating tauopathy symptoms using the fly as a model. We will next verify these effects of alterations in global protein glycosylation on AD pathology using human cultured cells over-expressing Aβ or tau and AD model mice.
