Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdepartmental Neuroscience Program

First Advisor

Strittmatter, Stephen

Abstract

Alzheimer’s disease (AD), the most common cause of dementia, is the 6th leading cause of death in the US and the 5th leading cause of death in individuals 65 and older. As the global population ages, current projections suggest that AD may overwhelm existing healthcare infrastructure in the 21st century, with cases in the US expected to surpass 13.8 million by 2060. The need for additional disease modifying therapies is paramount, though the development of novel therapeutic strategies for the treatment of AD is limited by our current understanding of AD pathophysiology. The vast majority of AD cases are sporadic in nature, with age being the single greatest risk factor, however a growing list of genetic risk factors identified through recent genome wide association studies (GWAS) has the potential to reveal key insights into the molecular mechanisms that govern AD susceptibility and mediate disease progression. Given that AD is defined by the pathological processing of both Aβ and Tau, any evaluation of a specific AD risk factor must consider the role that gene-product plays with respect to both proteins. Our group has previously reported that the AD risk factor Pyk2 is required for Aβ synaptotoxicity as well as the presentation of Aβ-associated phenotypes in AD animal models. Although Pyk2 has been previously shown to regulate kinases known to phosphorylate Tau at pathophysiologically-relevant residues (e.g. GSK3β and Fyn), and while at least one group has reported direct phosphorylation of Tau by Pyk2 through over-expression experiments, direct evidence demonstrating Pyk2-dependent modulation of Tau phosphorylation through the manipulation of endogenous Pyk2 is lacking. Experiments described here show that both genetic deletion and pharmacological inhibition of Pyk2 increases the phosphorylation of Tau at a number of pathophysiologically-relevant residues. Furthermore, genetic deletion of Pyk2 in PS19 animals that over-express a mutant form of human Tau associated with frontotemporal dementia significantly reduces animal survivorship, impairs memory and augments synaptic C1q deposition. These results suggest that, while Pyk2 contributes to toxic Aβ signaling, Pyk2 conversely suppresses Tau phosphorylation and Tau-associated phenotypes. To explore the mechanism by which Pyk2 suppresses Tau phosphorylation, we conducted phospho-proteomics on hippocampal synaptosomes from WT and Pyk2-/- animals, revealing a number of proximate regulators of Tau modulated by Pyk2 expression. From this list of six kinases, we confirm that the activity of at least one hit, LKB1, is suppressed by basal levels of Pyk2 activity. We also show that the activity of a direct substrate of LKB1 and a known kinase of Tau, p38 MAPK, is also inhibited by Pyk2. Revealingly, the activities of LKB1 and p38 MAPK are highest in PS190/+;Pyk2-/- mice, suggesting that the activities of these two kinases may at least partially explain the increased Tau phosphorylation and exacerbated Tau-associated phenotypes observed in these animals. While the implications of these data preclude Pyk2 as a promising pharmacological target using conventional therapeutic approaches, these results, in conjunction with previous results from our group, uncover a complex role for Pyk2 at the intersection of Aβ and Tau.

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