Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease

Abstract

One of the earliest pathological features characterizing Alzheimer’s disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini-Mental State Examination < 18 compared to age-matched non demented controls. The use of different constitutively active peptides allowed us to investigate in vitro Rac1 specific signaling. Its activation increased the processing of amyloid precursor protein and induced the translocation of SET from the nucleus to the cytoplasm, resulting in tau hyperphosphorylation at residue pT181. Notably, Rac1 was abnormally activated in the hippocampus of 6-week-old 3xTg-AD mice. However, the total protein levels decreased at 7-months. A rescue strategy based on the intranasal administration of Rac1 active peptide at 6.5 months prevented dendritic spine loss. This data suggests the intriguing possibility of a dual role of Rac1 according to the different stages of the pathology. In an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aβ and tau. However, at a later stage of the pathology, it might represent a potential therapeutic target due to the beneficial effect on spine dynamics.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0567-4) contains supplementary material, which is available to authorized users.

Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure

“…Rac1 is increased in plasma samples of AD patients [162] and, in the hippocampus of AD mice, Rac1 was abnormally activated at the early stages of the pathology, even if the total protein levels decreased at full-blown pathology stage. These data suggest that, in an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aβ and tau [162]. Evidence of actin involvement in AD comes from studies of the main neuropathological hallmarks of AD, i.e., neurofibrillary tangles and the senile plaque, and of the additional lesions that are detectable in AD brains, such as the Hirano bodies and the actin rods.…”

“…In neuronal cultures exposed to fibrillar Aβ peptide, an increased localization and activity of Rac1/Cdc42 Rho GTPases, promoted by Tiam1, were observed together with a consequent enhancement in actin polymerization [161]. Rac1 is increased in plasma samples of AD patients [162] and, in the hippocampus of AD mice, Rac1 was abnormally activated at the early stages of the pathology, even if the total protein levels decreased at full-blown pathology stage. These data suggest that, in an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aβ and tau [162].…”

The Role of Rac GTPase in Dendritic Spine Morphogenesis and Memory

“…Rac1 is also involved in another type of AD mice model, the 3xTg-AD. It is shown that Rac1 activity is increased in 6-week-old 3xTg-AD mice (Borin et al, 2018). Moreover, in primary cortical neurons, Rac1 or constitutively active mutant forms of Rac1 constructs led to the creation of pathogenic Aβ fragments and the translocation of SET from the nucleus to the cytoplasm, which also resulted in increased phosphorylation of tau.…”

Association between thiopurine medication exposure and Alzheimer's disease among a cohort of patients with inflammatory bowel disease

“…Regulation of Rac1 is a key determinant of neurologic health and is implicated in several neurologic diseases, including AD [5][6][7][8][9][10][11]. Given the wealth of preclinical evidence and the scarcity of human studies of Rac1 and AD, we sought to evaluate the association between Rac1 inhibitors, thiopurines, and incident AD diagnosis.…”

“…Rac1 has been implicated in Alzheimer's disease (AD) process [5], leading to increased amyloid precursor protein (APP) processing and stimulated tau hyperphosphorylation [6]. Evidence suggests Rac1 deregulation may be an AD trigger due to its effect on both APP and tau [6]. Furthermore, Rac1 inhibition in vascular endothelial cells could confer neuroprotection through the upregulation of artemin, a neurotrophic factor [7].…”