In vivo and in vitro Drosophila models to study the role of heparan sulfate in Alzheimer´s disease pathogenesis

Purpose and goal

A neuropathological hallmark of Alzheimer´s disease (AD) is the accumulation of extracellular amyloid plaques that are primarily composed of Amyloid- peptides (A). A is a heparin/heparan sulfate (HS)-binding protein, and HS affects multiple aspects of AD pathogenesis. However, the mechanisms by which HS affects A deposition, internalization, and clearance, remain to be elucidated. Our study aims at understanding how HS modifications (such as sulfation) affect each step of AD pathogenesis.

Expected results and effects

AD is the most common form of dementia, which disrupts memory, thinking and behavior. The cause of Alzheimer´s disease is poorly understood and no treatment to stop or reverse its progression has been established. Our study indicates that specific HS fine structures play critical roles at different steps of AD pathogenesis. Our findings provide novel insights into mechanisms of the disease and a knowledge foundation for the future development of AD treatments and therapies.

Planned approach and implementation

We combined a Drosophila AD model expressing a mutated human APP gene and animals that are mutated in HS biosynthesis. The effects of different HS structures on A-dependent neuronal degeneration phenotypes were analyzed. We also created Drosophila cell lines mutant for HS modifying enzymes. We will continue to use these cell lines to define how specific HS fine structures play critical roles at different steps of AD pathogenesis.