Journal
MOLECULAR NEUROBIOLOGY
Volume 59, Issue 6, Pages 3721-3737Publisher
SPRINGER
DOI: 10.1007/s12035-022-02810-w
Keywords
Epilepsy; Alzheimer's disease; Tau hyperphosphorylation; Insulin resistance; Memory
Categories
Funding
- Sao Paulo Research Foundation - FAPESP [17/21155-3, 19/02787-4, 19/05957-8, 19/16574-2, 19/00849-2]
- National Institutes for Science and Technology (INCT) - Translational Medicine
- FAPESP [14/50891-1]
- National Council for Scientific and Technological Development (CNPq) [465458/2014-9]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) [001]
- CNPq [305883/2014-3]
- Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior - PROEX-CAPES
- CNPq Research Fellowship
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [17/21155-3, 19/02787-4, 19/05957-8, 19/00849-2, 19/16574-2, 14/50891-1] Funding Source: FAPESP
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This study explores the behavioral and molecular alterations related to Alzheimer's disease in a genetic model of epilepsy. The findings indicate a partial AD-like phenotype, characterized by altered insulin signaling, in the epilepsy model. The study contributes to the understanding of the connection between epilepsy and AD, highlighting potential therapeutic targets.
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.
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