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
Description: 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)
Funding type: grant
Funder scheme: Auxílio à Pesquisa - Regular
Start date: 2025-02-01
End date: 2028-01-31
Investigator: Norberto Garcia Cairasco
Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (FMRP)
Funded outputs count: 5
Funder award ID: 24/16992-7
OpenAlex ID: G1906120843