Altered Distribution of RhoA in Alzheimer's Disease and AβPP Overexpressing Mice

Abstract

RhoGTPases control cytoskeleton dynamics thereby modulating synaptic plasticity. Because Alzheimer's disease (AD) is characterized by synaptic dysfunction, we sought to determine whether the expression, activity, or localization of the GTPases RhoA, Rac1 and Cdc42, as well as p21-PAK, a downstream target of Rac1/Cdc42, were altered in 18-month-old AbetaPP Tg2576 mice (Swedish mutation) or in brains from patients with AD and, for comparison in the case of RhoA, Pick's disease (PiD), a neurodegenerative disorder characterized by hyper-phosphorylated tau accumulation. Immunohistochemical analyses revealed a distinct localization of each RhoGTPase in synapses, dendrite shafts, neuronal bodies, or astrocytes. The association of RhoA with synapses and dendritic microtubules was confirmed by electron microscopy. In AbetaPP mice, RhoA expression decreased in synapses and increased in dystrophic neurites, suggesting altered subcellular targeting of RhoA. In AD, RhoA immunostaining decreased in the neuropil and markedly increased in neurons, co-localizing with hyperphosphorylated tau inclusions, as though RhoA were sequestered by neurofibrillary tangles. Additionally, total RhoA protein was lower in the AD brain hippocampus, reflecting loss of the membrane bound, presumably active, GTPase. RhoA colocalized with hyperphosphorylated tau in PiD, again suggesting that altered subcellular targeting of RhoA is related to neurodegeneration. No major immunohistochemical changes were observed for Rac1, Cdc42, or p21-PAK, thus identifying RhoA among RhoGTPases as a possible therapeutic target in AD.

NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

“…RhoA expression decreased in synapses and increased in dystrophic neuritis in AβPP mice [241], which could be the consequence of RhoA-expressing bouton loss. In addition, ROCK inhibition improves rotarod performance and reduces huntingtin levels in a mouse model of HD [242].…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…Recent immunohistological studies suggest that the subcellular localization of RhoA may be altered in AD brains, with decreased staining in the neuropil and a marked increase in neurons, co-localizing with hyperphosphorylated tau inclusions [30]. Localization of Rac1 and Cdc42 were reported to be unchanged.…”

“…Localization of Rac1 and Cdc42 were reported to be unchanged. RhoA mislocalization can also be seen in the human amyloid precursor protein (hAPP) Tg2576 (Swedish mutation) AD mouse model, which shows decreased levels in synapses but increased levels in dystrophic neurites [30]. At 12-18 months of age, these mice have also been reported to have significantly increased RhoA levels and decreased Rac1 levels in the brain [31].…”

RhoGTPase Regulators Orchestrate Distinct Stages of Synaptic Development

“…Altered RhoGTPase signaling leads to abnormal spine morphology and synaptic development and appears to contribute to the pathology of neuronal disorders, such as Autism Spectrum Disorders and non-syndromic mental retardation, as well as neurodegenerative disorders, like Alzheimer’s disease (AD) [12–16]. …”