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

• Document type: Journal article
• Source: Molecular Neurobiology; v. 59, n. 6, p. 17-pg., 2022-04-04.

Abstract

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)

• FAPESP's process: 19/05957-8 - Epilepsies and neuropsyquiatric comorbidities: characterization of the effects of the treatment with cannabidiol and HUF-101 in in vivo and in vitro experimental models
• Grantee: Norberto Garcia Cairasco
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/50891-1 - INCT 2014: Translational Medicine
• Grantee: Jaime Eduardo Cecilio Hallak
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/16574-2 - Unraveling the molecular and genetic mechanisms of epilepsy
• Grantee: Norberto Garcia Cairasco
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/02787-4 - Effects of cannabidiol vehiculated in nanoemulsion in rats submitted to the chemical model of temporal lobe epilepsy
• Grantee: Gabriel Servilha Menezes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 19/00849-2 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Rui Milton Patrício da Silva Junior
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/21155-3 - Wistar audiogenic rat (WAR): a possible model for the study of Alzheimer's Disease related to insulin resistance
• Grantee: Suélen Santos Alves
• Support Opportunities: Scholarships in Brazil - Master