Impact of Physical Exercise on Klotho Secretion by the Choroid Plexus: Mechanisms Mediated by Serotonin

• Grant number: 25/05309-7
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Elisa Mitiko Kawamoto Iwashe
• Grantee: Josiane do Nascimento Silva
• Supervisor: Cecilia Reis Alves dos Santos
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Universidade da Beira Interior (UBI), Portugal
• Associated to the scholarship: 24/03766-9 - Study of modulator function of klotho protein in neuroinflammatory signaling in mice, BP.PD

Abstract

The Central Nervous System (CNS) is responsible for regulating essential physiological functions and plays a crucial role in behavior and cognitive abilities. An important component in this context, although little explored, is the choroid plexus (ChP), located between the walls of the cerebral ventricles. The ChP is responsible for the production and secretion of cerebrospinal fluid (CSF), functioning as a barrier between the blood and CSF. In addition, the ChP is a source of bioactive molecules that influence brain homeostasis and neuronal function, notably the Klotho protein. Klotho has been associated with longevity, neuroprotection, and regulation of cellular processes, being especially relevant in the context of brain aging and neurodegenerative diseases. Klotho is mainly expressed in the kidney and brain, with ChP being one of its main sources. The protein has two forms: transmembrane (m-KL), associated with the regulation of phosphate and vitamin D homeostasis, and soluble (s-KL), which plays an important role in protection against oxidative stress and neuroprotection. Studies suggest that physical exercise can increase Klotho production and offer benefits to CNS health, such as cognitive improvements, neuroplasticity, and increased neurogenesis. Although most research on the impact of exercise on Klotho expression has focused on peripheral tissues, some evidence suggests that aerobic exercise may increase Klotho levels in the brain, especially after prolonged periods of activity. Additionally, serotonin (5-HT), a neurotransmitter important in cognition and neuroplasticity, has been implicated in modulating Klotho secretion. ChP has receptors for 5-HT, and studies indicate that exercise may increase 5-HT levels in the brain, suggesting that this interaction may play an important role in modulating Klotho secretion. However, the exact mechanism by which exercise and 5-HT influence Klotho production in ChP is still poorly understood. This project aims to investigate the influence of exercise on Klotho secretion by ChP and explore the modulatory role of 5-HT in this process. The study will be performed in male mice and will employ experimental approaches, such as aerobic exercise (treadmill running), immunofluorescence, 5-HT neuron lesioning by stereotaxis, and analysis of intracellular calcium concentrations using FURA-2. This study aims to understand how exercise and 5-HT interact to potentiate the neuroprotective effects of Klotho, which may open new perspectives for strategies for the prevention and treatment of neurodegenerative diseases.