Age is the primary risk factor for numerous neurodegenerative diseases, with Alzheimer?s disease (AD) being the most prevalent. During aging there is a decline in protein quality control systems which likely contributes to the formation of the molecular hallmarks of AD; with the accumulation of pathological tau species being a key feature of the disease. Dysfunction of autophagy and mechanisms that promote protein solubility occur early in the pathogenesis of AD. Impairment of these pathways likely contributes to the accumulation and mislocalization of tau, which plays a fundamental role in the pathogenesis of AD. Recent data provide compelling evidence that the stress responsive, small heat shock protein B8 (HspB8) plays a key role in maintaining proteostasis; decreased levels result in increases in insoluble proteins and decreases in autophagy. In addition, a recent study revealed that HspB8 and the multidomain Bcl2 associated athanogene 3 (BAG3) are expressed at higher levels in inhibitory neurons which are more resistant to tau pathology. These findings are very intriguing given that HspB8 is a key binding partner of BAG3, and thus they may work together to promote tau proteostasis. Further, our preliminary data suggest that HspB8 likely plays a key role in maintaining tau solubility and promoting autophagy. The UNDERLYING PREMISE of this proposal is that in neurons HspB8 plays a critical role in mediating tau solubility and autophagy, and thus the turnover of tau. The importance of HspB8 in mediating neuronal proteostasis is illustrated by the fact that previous findings indicate that HspB8 facilitates the autophagic clearance of disease relevant, aggregate prone proteins such as truncated TDP-43 species. Nonetheless, our understanding of how HspB8 regulates tau clearance and solubility is very limited. CRITICAL KNOWLEDGE GAPS include: how HspB8 levels affect tau solubility and accumulation, the role of HspB8 in modulating autophagic flux/ autophagosome-lysosome fusion, and if the expression level of HspB8 in neuronal populations correlates with their relative susceptibility to tau pathology. Considering these critical knowledge gaps the OVERALL HYPOTHESIS of this proposal is that HspB8 plays a role in maintaining tau solubility and facilitating autophagic flux, and thus tau clearance. In the context of this overall hypothesis the specific aims of this proposal are: (1) To test the hypothesis that HspB8 mediates tau solubility and autophagic flux and thus contributes to tau clearance in a BAG3 dependent manner, (2) To test the hypothesis that HspB8 is differentially expressed in inhibitory and excitatory neurons which plays a role in determining susceptibility to tau pathology, and (3) To test the hypothesis that HspB8 protects neurons from tau pathology in vivo. The majority of these studies will be carried out using primary neuron cultures and mouse models. All in vivo studies will be carried out in older male and female mice since age likely influences the effects of HspB8. The IMPACT of these studies will be to provide crucial new insights into the mechanisms by which HspB8 protects against tau accumulation and facilitates turnover by autophagy to maintain a healthy neuron.
Understanding the normal physiological processes that govern the clearance of damaged proteins in neurons is of fundamental importance in the context of age. In this proposal we are focused on understanding the HspB8 dependent mechanisms regulating vacuolar dependent degradative pathways and the turnover of tau in neurons. The results from these studies will provide foundational information for understanding the mechanisms that contribute to the development of tau pathology in Alzheimer?s disease and other neurodegenerative diseases.
