All ETDs from UAB

Advisory Committee Chair

Jeremy H Herskowitz

Advisory Committee Members

Jeremy Day

Haydeh Payami

Erik Roberson

Qin Wang

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Current estimates project that there are approximately 5.4 million Americans affected by Alzheimer’s disease (AD). While this number is expected to dramatically increase in the years to come, there is currently no disease modifying therapeutic to prevent or slow AD progression. Cognitive decline is a clinical hallmark of AD, while accumulation of amyloid-β (Aβ) is a pathological hallmark. Work in the field has demonstrated that mitigating Aβ levels may serve as a rational therapeutic avenue to slow progression of the disease. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that underlie ROCK2's effects on Aβ production are defined. My work here demonstrates that ROCK1 protein levels are increased in mild cognitive impairment due to AD (MCI) and AD cases, and that Aβ activates the RhoA/ROCK pathway. Here I show that, contrary to published work, ROCK1 reduction diminishes Aβ levels by enhancing APP protein degradation. This work supports a hypothesis that both ROCK1 and ROCK2 are potentially viable therapeutic targets for the reduction of Aβ in AD. Downstream of Aβ, dendritic spine loss correlates most strongly with cognitive decline in AD. However, there are no current therapeutic strategies that target synapse loss as a mechanism to prevent or slow cognitive decline in AD. Work in this dissertation has demonstrated that Aβ induces the activity of ROCK1 and ROCK2, and that ROCK protein levels are in increased in AD progression. ROCK1 and ROCK2 are potent regulators of actin dynamics, and I show here that ROCK1 reduces dendritic spine length through a myosin-based pathway, while ROCK2 induces spine loss through LIM kinase (LIMK). Using static and live-cell imaging techniques along with multi-electrode array (MEA) analyses, I show in this dissertation that Aβ induces dendritic spine degeneration as well as neuronal hyperexcitability. Inhibition of the ROCK2-LIMK signaling pathway can prevent these phenotypes. Furthermore, I show that inhibiting the ROCK2-LIMK pathway in amyloidosis mice is sufficient to rescue Aβ-induced spine loss. Work here highlights an exciting new therapeutic avenue to combat cognitive decline in AD.

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