Glycosaminoglycans (GAGs) are a family of negatively charged linear polysaccharides, which have been found in the cores of protein aggregates that are central pathological features in several neurodegenerative diseases including Alzheimer's Disease (AD). Furthermore, GAGs are shown to be critical in the aggregation, internalization and propagation of pathogenic aggregates. Neurotoxic protein aggregates are mostly comprised of phosphorylated tau proteins that are resistant to proteolytic cleavage and are found in all AD patients. Recent studies have shown that blueberry metabolites possess beneficial neuroprotective effects in animal models and in limited clinical studies. Our own lab has recently found that blueberry metabolites can restore endothelial heparan sulfate (HS), one type of GAG, and ameliorates endothelial inflammation in diabetic endothelial cells. Taken together the role of blueberry metabolites in the regulation of HS fine structures and their beneficial neuroprotective effects, we hypothesize that blueberry metabolites exert their beneficial effects through regulation of HS biosynthesis in the brain by regulating HS structures in the brain microvascular endothelial cells and neuronal cells. In this supplemental request, we propose to systematically study the role of blueberry diet and blueberry metabolites in the reversal of neurotoxic effects of tau aggregates in cellular and primary neuronal cultures through regulation of HS fine structures with the final goal of developing a therapeutic approach for AD prevention and management.
Regulation of glycosaminoglycan biosynthesis is critical as glycosaminoglycans have been implicated in numerous biological and pathological processes including neurodegeneration, neurogenesis, axon guidance and axonal regeneration as well as learning/memory. We can fine-tune pathological processes associated with Alzheimer's Disease (AD) and related dementia (ADRD) through manipulation of extracellular matrix derived glycosaminoglycan composition, particularly heparan sulfate fine structures, using blueberry derived metabolites. This proposal aims to study the benefits of blueberry diet in treating various AD and ADRD, and also elucidate the underlying molecular mechanism. In summary, the proposed supplemental work will accelerate a development of blueberry derived metabolites to treat millions of humans in USA and worldwide who suffer from AD/ADRD for which no cure exists at present.
