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