Spatial dysregulation of Rho GTPases in Alzheimer’s Disease brain in human and in transgenic mouse model

Abstract

AbstractBackgroundAlzheimer disease (AD) is histopathologically characterized by brain accumulation of amyloid plaques, neurofibrillary tangle formation, and loss of synapses. The small GTPases of Rho family such as RhoA, Rac1 and Cdc42 play an important role in neural plasticity by regulating synaptic actin and spine dynamics. However, the functions of these proteins in AD are paradoxical. To understand their contributions in AD pathogenesis, it is important to investigate the relationship between the expression of Rho GTPases and their functional states in signaling.MethodWe characterized the spatial dysregulation of Rho GTPases in human AD brains and that of aged Triple Transgenic (3xTg‐AD) mouse model carrying mutations in amyloid precursor protein, tau protein, and presenilin. For human brains, the paraffin‐embedded tissues were collected from age and gender matched AD and Non‐Dementia (ND) patients. Phosphorylated Rho GTPase antibodies were used as signaling indicators for immunofluorescence microscopyResultWe observed altered phospho‐RhoA (S188) and phospho‐Rac/Cdc42(S71) expression and distribution in human, wild type (WT), and 3xTg‐AD mouse brains. In the CA3 region and dentate gyrus (DG), pRac/Cdc42 immunostaining showed decreased punctate staining in WT compared to 3xTg‐AD mice. For CA3 pRhoA immunostaining scored a slightly higher level of expression in WT compared to 3xTg‐AD. In the CA2 region, pRac/Cdc42 immunostaining was perinuclear in WT and diffused in 3xTg‐AD, whereas the pRhoA immunostaining pattern was similar between WT and 3xTg‐AD. In the CA1 region, pRac/Cdc42 immunostaining showed perinuclear as well as dendritic localization in WT and 3xTg‐AD, while pRhoA immunostaining between WT and 3xTg‐AD was similar. In human brains,there was no significant difference in pRhoA in cortex between ND and AD whereas pRac/Cdc42 was slightly reduced in AD cortex. However, while Rac signaling was reduced, Cdc42 signaling was increased in ND compared to AD cortex. On the other hand, Rac signaling is decreased in ND DG compared to AD whereas the differences in Cdc42 signaling in DG were not significant.ConclusionSmall GTPases of Rho family are differentially dysregulated in expression, distribution, and functional states in different areas of the brain in AD patients as well as in AD mouse brains