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

Issue title: Similarities and Differences Between Mild Cognitive Impairment and Alzheimer's Disease

Guest editors: Mark A. Lovell

Article type: Research Article

Authors: Huesa, Gema^a | Baltrons, María Antonia^b | Gómez-Ramos, Pilar^c | Morán, Asunción^c | García, Agustina^b | Hidalgo, Juan^{a; d} | Francés, Silvia^a | Santpere, Gabriel^e | Ferrer, Isidre^e | Galea, Elena^{a; f; *}

Affiliations: [a] Institut de Neurociènces, Universitat Autònoma de Barcelona, Spain | [b] Institut de Biotecnologia i Biomedicina “Villar Palasí”, Departament de Bioquímica i Biologia Cellular, Universitat Autònoma de Barcelona, Spain | [c] Departamento de Anatomía, Histología y Neurociencia, Universidad Autónoma de Madrid, Spain | [d] Unitat de Fisiologia Animal, Departament de Biologia Cellular, Fisiologia i Inmunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Spain | [e] Institut de Neuropatologia, Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, CIBERNED, Spain | [f] Institut Català d'Estudis Avançats (ICREA), Spain | Sanders-Brown Center on Aging and Alzheimer's Disease Center, Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA

Correspondence: [*] Corresponding author: Elena Galea, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Tel.: +34 93 581 8143; Fax: +34 93 581 1572; E-mail: Elena.Galea@uab.es.

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 AβPP 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 AβPP 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.

Keywords: Actin, cytoskeleton, microtubules, neurofibrillary tangles, Pick's disease, synaptic terminals, tau

DOI: 10.3233/JAD-2010-1203

Journal: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 37-56, 2010