title: Altered distribution of RhoA in Alzheimer's disease and AbetaPP 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.
authors.affiliation: Institut de Neurociènces, Universitat Autònoma de Barcelona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Huesa
authors.forename: María Antonia
authors.initials: MA
authors.lastname: Baltrons
authors.forename: Pilar
authors.initials: P
authors.lastname: Gómez-Ramos
authors.forename: Asunción
authors.initials: A
authors.lastname: Morán
authors.forename: Agustina
authors.initials: A
authors.lastname: García
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.forename: Silvia
authors.initials: S
authors.lastname: Francés
authors.forename: Gabriel
authors.initials: G
authors.lastname: Santpere
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Elena
authors.initials: E
authors.lastname: Galea
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D020774:Pick Disease of the Brain / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D020742:rhoA GTP-Binding Protein