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.

Keywords: AD mouse model; AD therapy; Alzheimer’s disease; Cdc42; NSAIDs; Rac1; Rho GTPases; RhoA.

Fig. 1

Rho GTPases and AD pathology. a Amyloid precursor protein (APP) can undergo amyloidogenic (right) or non-amyloidogenic (left) processing. In the amyloidogenic pathway, β-secretase cleavage results in the formation of soluble APPβ (sAPPβ). Cleavage by γ-secretase forms β-amyloid (Aβ) and amyloid precursor protein intracellular domain (AICD). Accumulation of Aβ leads to amyloid plaque formation. Several studies have reported the activation loop between Aβ and Rho GTPases (green arrows). Activated Rac1 can increase APP production and promote the amyloidogenic pathway by modifying β-secretase selectivity for APP (green arrows). In the non-amyloidogenic pathway, α-secretase cleaves within the Aβ region, which results in the formation of sAPPα. Cleavage by γ-secretase forms the P3 peptide and AICD. Activation of Rac1 via the 5-HT₄/cAMP/Epac/Rap/Rac1 signaling cascade promotes the formation of sAPPα (purple arrows). b RhoA activates ROCK that can phosphorylate tau (Thr245 and Ser409) leading to neurofibrillary tangle (NFT) and microtubule destabilization. 5-HT serotonin, cAMP cyclic adenosine monophosphate, Epac exchange proteins directly activated by cAMP, Rap1 Ras-proximate-1/Ras-related protein-1, RhoA Ras homolog gene family, member A, ROCK Rho-associated protein kinase