Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Program in Neuroscience, 2015.
Alzheimer disease (AD) is the leading cause of neurodegeneration worldwide. Unfortunately, there are limited therapeutic options, due in part to an incomplete understanding of disease pathogenesis. One pathological hallmark of AD is the intracellular accumulation of hyperphosphorylated and truncated forms of the microtubule associated protein tau. These pathological forms of tau cannot appropriately interact with microtubules and also cause neuronal damage. Impaired protein degradation is likely a factor in tau accumulation in AD. Therefore, interventions that selectively facilitate the clearance of pathological tau are of significant interest. Evidence suggests some modified forms of tau are preferentially cleared via the autophagy pathway. One aim of this project was to further clarify how different forms of tau are cleared through the use of novel stable cell lines expressing one of several known AD-relevant modifications: either truncation at aspartate 421 or phosphorylation at threonine 231 or serine 262. An additional aim was to investigate potential ways to enhance the clearance of phosphorylated tau. Phytochemicals are bioactive compounds found in common foods like green tea and cruciferous vegetables. Because of their ready availability and low toxicity profile, phytochemicals are attractive to explore as novel therapeutics. Several phytochemicals are able to activate the protective Nrf2 pathway, and these Nrf2 activators have shown promise in mitigating amyloid pathology in vitro and in vivo. A recent study showed the isothiocyanate sulforaphane (SFN) can reduce phosphorylated tau in an autophagy-dependent manner. The flavonoid epigallocatechin-3-gallate (EGCG) has shown anti-amyloidogenic properties, but its effect on tau pathology has not been assessed. This study demonstrated that EGCG can enhance the clearance of phosphorylated tau species in a primary neuron culture
model. Interestingly, the protein clearance effect appeared to be independent of the Nrf2 pathway, as EGCG had limited Nrf2 activator activity in primary neurons. Additionally, EGCG did not enhance autophagy as a general process, but did significantly increase mRNA expression of the key autophagy adaptor proteins NDP52 and p62. Taken together, these results demonstrate EGCG has the ability to clear phosphorylated tau species in a highly specific manner, likely through increasing in adaptor protein expression.
