Rho GTPases as therapeutic targets in Alzheimer’s disease

Abstract

The progress we have made in understanding Alzheimer’s disease (AD) pathogenesis has led to the identification of several novel pathways and potential therapeutic targets. Rho GTPases have been implicated as critical components in AD pathogenesis, but their various functions and interactions make understanding their complex signaling challenging to study. Recent advancements in both the field of AD and Rho GTPase drug development provide novel tools for the elucidation of Rho GTPases as a viable target for AD. Herein, we summarize the fluctuating activity of Rho GTPases in various stages of AD pathogenesis and in several in vitro and in vivo AD models. We also review the current pharmacological tools such as NSAIDs, RhoA/ROCK, Rac1, and Cdc42 inhibitors used to target Rho GTPases and their use in AD-related studies. Finally, we summarize the behavioral modifications following Rho GTPase modulation in several AD mouse models. As key regulators of several AD-related signals, Rho GTPases have been studied as targets in AD. However, a consensus has yet to be reached regarding the stage at which targeting Rho GTPases would be the most beneficial. The studies discussed herein emphasize the critical role of Rho GTPases and the benefits of their modulation in AD.

Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

“…This approach revealed a novel miR-132-specific molecular signature consisting of DOCK1, EPHB3, BTG2, CAMK1 and RAC1 , all of which have reported roles in neuronal differentiation and function (Fortin et al, 2010; Goold and Nicoll, 2010; Pillat et al, 2016; Theus et al, 2010; Vadodaria et al, 2013; Yang et al, 2012). Dock1, Ephb3, Camk1 and Rac1 have additionally been implicated in AD (Aguilar et al, 2017; Becker et al, 2014; Overk and Masliah, 2014; Riascos et al, 2014), while all five proteins have been associated with the immune response in a variety of cells (D’Ambrosi et al, 2014; Goold and Nicoll, 2010; Guo et al, 2013; Naskar et al, 2014; Pillat et al, 2016; Theus et al, 2010; Yuniati et al, 2018). Interestingly, miR-132 knockdown also repressed the running-induced increase of Bdnf , a key neurotrophic factor contributing to the fitness of the niche and the neurogenic potential.…”

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

“…Dysfunction of these pathways has been observed in AD leading to characteristic accumulation of APP and Aβ (16). MYO9A is an unconventional myosin responsible for the regulation of Rho GTPase activity within neurons, which in turn regulates neuronal morphology and function; for these reasons, the Rho family has been a recent therapeutic target for neurodegenerative diseases such as AD (17). In turn, various Rho GTPases have also been implicated in maintenance of mitochondrial homeostasis and apoptotic signaling (18).…”

Molecular inflection points in the aging human brain

“…GTPases are regulators of the cytoskeleton and mediate diverse neuronal processes [21]. Changes in the regulation of both MAPK signaling and GTPase activity have been implicated in the development of many neurodegenerative diseases [22,23].…”