The role of rho-gtpases in the aetiology of Alzheimer's disease

AIMS: The progression of Alzheimer’s disease (AD) is characterized by a wide synaptic and dendritic loss whose mechanisms are still unknown. We aimed at studying the potential role of Rho-GTPases, key regulator of spine dynamics, as biomarkers for AD and interacting partners of tau and beta-amyloid peptide (Abeta). METHOD: Rac1 and Cdc42 levels were measured by ELISA in the plasma of AD patients (n=101), age and sex-matched healthy controls (n=102) as well as in frontal cortex of autoptic brain samples. The 3xTgAD mouse model was used to correlate the alteration of Rho-GTPases in the brain to the progression of the disease. To investigate the molecular mechanisms connecting Rho-GTPases to Abeta and tau, mouse primary cortical neurons were treated with Rho-GTPase mutant proteins, Rac1 and Cdc42, and immunocytochemistry and pull down assays were performed. RESULTS: Rac1 was significantly increased in plasma of AD patients and significantly decreased in AD brain homogenates compared to controls. The underlined involvement of Rac1 was confirmed by the decreased levels of Rac1 in the cortex of 7 month old 3xTgAD. Rac1 deregulation affected Aß metabolism and tau regulators. CONCLUSION: Our data proposes a putative pathway in which Rac1 is able to affect the regulation of AD relevant proteins. Moreover, we show that Rac1 is increased in AD plasma suggesting its novel role as a biomarker for AD and as a promising therapeutic target.