Insulin signaling disruption exacerbates memory impairment and seizure susceptibility in an epilepsy model with Alzheimer's disease-like pathology

Author(s)

Alves, Suelen Santos ; Servilha-Menezes, Gabriel ; Rossi, Leticia ; de Oliveira, Jose Antonio Cortes ; Grigorio-de-Sant'Ana, Mariana ; Sebollela, Adriano ; da Silva-Junior, Rui Milton Patricio ; Garcia-Cairasco, Norberto

• Document type: Journal article
• Source: JOURNAL OF NEURAL TRANSMISSION; v. N/A, p. 22-pg., 2025-02-22.

Abstract

Alzheimer's disease (AD) and epilepsy exhibit a complex bidirectional relationship. Curiously, diabetes as a comorbidity increases the risk of epilepsy among AD patients. Recently, we reported that the Wistar audiogenic rat (WAR) strain, a genetic model of epilepsy, displays a partial AD-like phenotype, including brain insulin resistance. We also assessed seizure susceptibility in an AD model created through intracerebroventricular injections of streptozotocin (icv-STZ), which induces AD features via brain insulin resistance. Our goal was to explore how disrupted brain insulin signaling influences AD-like features and seizure susceptibility in the WAR strain. Adult male WARs received a single intracerebroventricular injection of streptozotocin (icv-STZ) (1.5 mg/kg) or vehicle (saline). Two weeks post-injection, spatial memory was assessed using the Barnes Maze (BM) test. Three weeks later, the rats underwent an audiogenic kindling (AuK) protocol (20 acoustic stimuli, 2 per day) to evaluate seizure frequency and severity. Seizures were analyzed using the Categorized Severity Index and Racine's scale and Western blot analysis was performed on hippocampal tissue. Our findings revealed that icv-STZ significantly worsened memory performance, increased seizure frequency, and reduced seizure onset relative to vehicle. Furthermore, icv-STZ decreased Akt activation and increased Glycogen Synthase Kinase-3 (GSK3) phosphorylation, indicating disrupted insulin signaling. Notably, icv-STZ decreased tau phosphorylation without altering amyloid beta precursor protein (A beta PP) levels. In conclusion, a low-dose icv-STZ injection exacerbates memory deficits and seizure susceptibility in the WAR strain by disturbing downstream proteins involved in insulin signaling. This highlights the implications of brain insulin resistance in both AD and epilepsy. (AU)

• 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: 19/05957-8 - 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: 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
• FAPESP's process: 14/50891-1 - INCT 2014: Translational Medicine
• Grantee: Jaime Eduardo Cecilio Hallak
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/00849-2 - 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: 24/16992-7 - EXPLORING THE BIDIRECTIONAL RELATIONSHIP BETWEEN ALZHEIMER'S DISEASE AND EPILEPSY. AN ANALYSIS OF ALTERATIONS IN THE BRAIN INSULIN SIGNALING PATHWAY AS A POTENTIAL MECHANISM OF CONNECTION BETWEEN THE TWO CONDITIONS
• Grantee: Norberto Garcia Cairasco
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/13622-6 - Assessing anxiety and painful hypersensitivity as comorbidities associated with Epilepsy: effects of cannabidiol treatment and the role of CB1, TRPV1 and 5-HT1A receptors
• Grantee: Willian Lazarini Lopes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/10925-8 - Neurotoxic beta-amyloid peptide oligomers: biochemical isolation, conformational studies and neutralization in Alzheimer's Disease models
• Grantee: Adriano Silva Sebollela
• 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