ANALYSIS OF THE EFFECT OF LITHIUM ON MICROGLIAL MORPHOLOGY IN ALZHEIMER'S DISEASE

• Grant number: 25/00540-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Leda Leme Talib
• Grantee: Julia Santos de Almeida Lima
• Host Institution: Instituto de Psiquiatria Doutor Antonio Carlos Pacheco e Silva (IPq). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Ageing is a natural process associated with structural and functional neurobiological changes which, linked to increasing age, can become dysfunctional. Interest in the health care of the elderly is due to the fact that they are the fastest growing demographic group and are the most exposed to chronic diseases, such as neurodegenerative diseases associated with dementia. Around 70% of dementia cases are due to Alzheimer's disease (AD). AD is characterized by the deposition of ¿-amyloid (¿A) plaques and neurofibrillary tangles (NFs) resulting in impaired neuron function, neuroinflammation and, ultimately, cell apoptosis. In an inflammatory environment, the brain's immune response activates microglia, one of the nervous system's main defense cells. Microglia, in response to factors such as cytokines, can assume the M1 or M2 phenotype. Polarization towards the M1 phenotype is associated with neurotoxicity, while M2 favours neuroprotection. In neurodegenerative conditions, the microglial phenotype of interest for favoring neuroprotection is the M2 state. Therefore, a pharmacological compound capable of modulating the microglial phenotype in favor of neuroprotection could be a promising therapeutic strategy for AD. Known for its efficacy in the treatment of bipolar disorder, lithium salts are gaining increasing relevance in neurodegenerative diseases. This is due to the inhibitory action of the enzyme glycogen synthase kinase-3¿ (GSK-3¿) and other important pathways associated with the processes that aggravate AD, such as the formation of ¿A plaques, ENFs and microglial activation in its M1 phenotype. The inhibition of the GSK-3¿ enzyme due to the action of lithium directly reduces neurotoxic factors, modifying the neuropathological picture and may even induce the neuroprotective M2 microglial phenotype. Given the urgent need for potential strategies to modify AD, this study aims to analyze the effect of lithium treatment on the microglial phenotype of an animal model for AD. This will be done using a 12-month-old 3xTg-AD animal model submitted to chronic treatment with lithium carbonate (Li¿CO¿; 3 months; 1.0 mg/kg of feed). Changes and microglial proliferation will be assessed by immunolabeling of the Iba-1 molecule, a protein expressed in large numbers in microglial cells and macrophages, in important brain regions involved in AD. We propose to gather evidence to support the therapeutic use of lithium for AD.