A Genetic Model of Epilepsy with a Partial Alzheimer's Disease-Like Phenotype and Central Insulin Resistance

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Alves, Suelen Santos ; Patricio da Silva Junior, Rui Milton ; Delfino-Pereira, Polianna ; Alves Goulart Pereira, Marilia Gabriella ; Vasconcelos, Israel ; Schwaemmle, Hanna ; Mazzei, Rodrigo Focosi ; Carlos, Maiko Luiz ; Espreafico, Enilza Maria ; Tedesco, Antonio Claudio ; Sebollela, Adriano ; Almeida, Sebastiao Sousa ; Cortes de Oliveira, Jose Antonio ; Garcia-Cairasco, Norberto

• Tipo de documento: Artigo Científico
• Fonte: Molecular Neurobiology; v. 59, n. 6, p. 17-pg., 2022-04-04.

Resumo

Studies have suggested an important connection between epilepsy and Alzheimer's disease (AD), mostly due to the high number of patients diagnosed with AD who develop epileptic seizures later on. However, this link is not well understood. Previous studies from our group have identified memory impairment and metabolic abnormalities in the Wistar audiogenic rat (WAR) strain, a genetic model of epilepsy. Our goal was to investigate AD behavioral and molecular alterations, including brain insulin resistance, in naive (seizure-free) animals of the WAR strain. We used the Morris water maze (MWM) test to evaluate spatial learning and memory performance and hippocampal tissue to verify possible molecular and immunohistochemical alterations. WARs presented worse performance in the MWM test (p < 0.0001), higher levels of hyperphosphorylated tau (S396) (p < 0.0001) and phosphorylated glycogen synthase kinase 3 (S21/9) (p < 0.05), and lower insulin receptor levels (p < 0.05). Conversely, WARs and Wistar controls present progressive increase in amyloid fibrils (p < 0.0001) and low levels of soluble amyloid-p. Interestingly, the detected alterations were age-dependent, reaching larger differences in aged than in young adult animals. In summary, the present study provides evidence of a partial AD-like phenotype, including altered regulation of insulin signaling, in a genetic model of epilepsy. Together, these data contribute to the understanding of the connection between epilepsy and AD as comorbidities. Moreover, since both tau hyperphosphorylation and altered insulin signaling have already been reported in epilepsy and AD, these two events should be considered as important components in the interconnection between epilepsy and AD pathogenesis and, therefore, potential therapeutic targets in this field. (AU)

• Processo FAPESP: 19/05957-8 - Epilepsias e comorbidades neuropsiquiátricas: caracterização dos efeitos do tratamento com canabidiol e HUF-101 em modelos experimentais in vivo e in vitro
• Beneficiário: Norberto Garcia Cairasco
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/50891-1 - INCT 2014: Translacional em Medicina
• Beneficiário: Jaime Eduardo Cecilio Hallak
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/16574-2 - Desvendando os mecanismos moleculares e genéticos da epilepsia
• Beneficiário: Norberto Garcia Cairasco
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/02787-4 - Efeitos do canabidiol veiculado em nanoemulsão em ratos submetidos ao modelo químico de epilepsia do lobo temporal
• Beneficiário: Gabriel Servilha Menezes
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 19/00849-2 - Mecanismos fisiopatológicos e moleculares de tumorigênese: abordagem baseada em plataformas de sequenciamento em escala genômica (NGS - Next-generation sequencing)
• Beneficiário: Rui Milton Patrício da Silva Junior
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/21155-3 - Wistar Audiogenic Rat (WAR): um possível modelo para o estudo da Doença de Alzheimer relacionada com resistência à insulina
• Beneficiário: Suélen Santos Alves
• Modalidade de apoio: Bolsas no Brasil - Mestrado