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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

Grant number: 24/16992-7
Support Opportunities:Regular Research Grants
Start date: February 01, 2025
End date: January 31, 2028
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Norberto Garcia Cairasco
Grantee:Norberto Garcia Cairasco
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated researchers:Adriano Silva Sebollela ; Bruno Antonio Benitez Viloria ; Christian Andrés Rojas Cerón ; Eduardo Rigon Zimmer ; Efraín Buriticá Ramirez ; Guilherme Gozzoli Podolsky Gondim ; Lina Vanessa Becerra Hernández ; Maria Elisa Calcagnotto ; Mark Oliver Cunningham

Abstract

Alzheimer's disease (AD), the most common type of dementia and the fourth leading cause of disability among people aged 75 and over, is a progressive neurodegenerative condition. It impairs memory and language and causes behavioral/psychiatric changes. Evidence from the literature and from the Laboratory of Neurophysiology and Experimental Neuroethology (LNNE), with experience in epilepsy/neuropsychiatric comorbidities, suggests central insulin resistance (CIR) and alterations in the insulin signaling pathway (VSI) as a bidirectional link between AD and epilepsy. There is clinical evidence of alterations in the VSI in patients with AD, but no evidence of alterations in the VSI in individuals with epilepsy. In this context, the LNNE demonstrated: (1) In the Wistar Audiogenic Rat (WAR) genetic model of epilepsy, there is spatial memory impairment/hyperphosphorylation of tau protein, and alterations in the VSI. (2) Streptozotocin (STZ; mimics diabetes and AD) predisposes to seizures. Antidiabetic drugs (e.g. metformin) attenuate the effects of STZ, and the mechanisms in the CNS are unknown. Therefore, understanding the processes by which STZ acts, and how antidiabetic drugs can control them, will clarify the link between AD, ICR and epilepsy.We propose: (1) To evaluate a model of AD, by icv-STZ (promoter of neural hyperexcitability). (2) To analyze the effects of icv-STZ administration (WARs) and verify the exacerbation of the partial phenotype of AD and audiogenic seizures, by altering the regulation of VSI proteins. (3) To verify whether chronic treatment with metformin in WARs attenuates the partial phenotype of AD and seizures. (4) To evaluate cerebral glucose metabolism by microPET in Sprague-Dawley rats and WARs, after icv-STZ. (5) Verify whether brain tissues (surgeries from patients with epilepsy) present alterations in the VSI, versus post-mortem tissues from patients with AD. (6) Investigate the application of STZ in human organotypic cultures to study RCI, and its impact on AD and epilepsy. (7) Record electrophysiological activity in organotypic cultures (human epileptogenic zones), to detect hyperexcitability in vitro. (8) Perform transcriptomics/proteomics of brain from WARs/Wistar, and in human tissue from patients with epilepsy/controls, to recognize molecular signatures of the AD and epilepsy link. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
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. Insulin signaling disruption exacerbates memory impairment and seizure susceptibility in an epilepsy model with Alzheimer's disease-like pathology. JOURNAL OF NEURAL TRANSMISSION, v. N/A, p. 22-pg., . (19/16574-2, 19/05957-8, 17/21155-3, 14/50891-1, 19/00849-2, 24/16992-7, 21/13622-6, 21/10925-8, 19/02787-4)
ALVES, SUELEN SANTOS; ROSSI, LETICIA; DE OLIVEIRA, JOSE ANTONIO CORTES; SERVILHA-MENEZES, GABRIEL; GRIGORIO-DE-SANT'ANA, MARIANA; MAZZEI, RODRIGO FOCOSI; ALMEIDA, SEBASTIAO SOUSA; SEBOLLELA, ADRIANO; DA SILVA JUNIOR, RUI MILTON PATRICIO; GARCIA-CAIRASCO, NORBERTO. Metformin Improves Spatial Memory and Reduces Seizure Severity in a Rat Model of Epilepsy and Alzheimer's Disease comorbidity via PI3K/Akt Signaling Pathway. Molecular Neurobiology, v. N/A, p. 28-pg., . (21/10925-8, 24/16992-7, 19/02787-4, 17/21155-3, 14/50891-1, 19/05957-8, 19/16574-2, 19/00849-2, 21/13622-6)