Modulation of Kv 1.3 channel mechanics as a molecular target in Alzheimer's Disease

• Grant number: 24/10962-9
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2025
• End date: January 31, 2027
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Emidio Beraldo Neto
• Grantee: Emidio Beraldo Neto
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Alzheimer's disease (AD), the most common form of dementia, represents a major health challenge, affecting approximately 1.2 million Brazilians. It is a neurodegenerative condition marked by the presence of beta-amyloid plaques and neurofibrillary tangles, resulting in neuronal degeneration and progressive cognitive impairment. The lack of effective therapies highlights the need for new strategies, such as the modulation of Kv 1.3 potassium channels, which have emerged as promising targets for therapeutic interventions. This study aims to investigate the therapeutic effects of Kv 1.3 potassium channel blockers in cellular models of primary cell culture, with an emphasis on cell viability, neuroprotection, and molecular mechanisms, to develop new therapeutic strategies for AD.To understand the impact of Kv 1.3 blockers on AD-associated neurotoxicity, cell viability in the presence of beta-amyloid peptide will be studied. Simultaneously, label-free proteomic and metabolomic analyses will be conducted to identify molecular targets and biochemical pathways affected by the treatment, providing detailed insights into the mechanisms of action. Additionally, axonal development in SH-SY5Y cells will be evaluated using anti-MAP2 and anti-Beta-III Tubulin antibodies to identify direct neuroprotective effects. Finally, the phagocytic activity of microglia against beta-amyloid peptides will be analyzed using anti-CD68 staining and quantified by LC-MS, providing information on the compounds' ability to promote beta-amyloid clearance and reduce neuroinflammation.This study addresses multiple dimensions of AD pathology and the potential of Kv 1.3 blockers as effective modulators, providing a solid foundation for the development of new strategies against Alzheimer's disease. (AU)