Analysis of the involvement of lithium in mitochondrial markers in Alzheimer's Disease

• Grant number: 21/06378-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2022
• End date: February 28, 2026
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Orestes Vicente Forlenza
• Grantee: Monique Patricio Singulani
• 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

Alzheimer's disease (AD) is considered a major challenge in medical care and is the main cause of dementia characterized by neuronal loss associated with senile plaques and neurofibrillary tangles (NFT). In addition, mitochondrial dysfunction and anomalous GSK-3² activity have also been observed in AD. Therefore, lithium has been suggested as an important therapeutic strategy because it has neuroprotective effects through the inhibition of GSK-3², as well as modulation of mitochondrial biology. Therefore, our aim will be to analyze the therapeutic effects of lithium on mitochondrial biogenesis and function in AD. For this, the animal model 3xTg-AD with 3 and 9 months of age will be used and submitted to chronic treatment with lithium carbonate (Li2CO3; 3 months; 1.0 g / Kg of food). The evaluation of the histopathological progression and the cognitive impairment of the animals will be performed using the immunostaining technique for ²-amyloid and phosphorylated Tau and behavioral tests, respectively. In addition, we will evaluate the expression of proteins related to the GSK-3 pathway, such as Akt, Phospho-Akt, GSK-3±/², Phospho-GSK-3±/², to mitochondrial function and biogenesis, such as PKAC-±, CREB, Phospho-CREB, PGC-1±, NRF1, TFAM, OXPHOS and VDAC1, Bax and Bcl-2 to evaluate the pro and anti-apoptotic pathway. To analyze the bioenergetic parameters, techniques for determining the number of copies of mitochondrial DNA (mtDNA) and measuring levels of ATP/ADP, pyruvate/lactate, and NAD+/NADH will be performed. Lastly, through the comparative proteomics approach, we will evaluate the profile of differentially expressed proteins from the animal model for AD in the face of chronic treatment with lithium carbonate. We believe that this study can provide relevant subsidies for a better understanding of the use of lithium in mechanisms related to mitochondrial biology as a potential therapeutic strategy for the treatment and/or prevention of AD.

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)

SINGULANI, MONIQUE PATRICIO; FERREIRA, ANA FLAVIA FERNANDES; FIGUEROA, PAULINA SEPULVEDA; CUYUL-VASQUEZ, IVAN; TALIB, LEDA LEME; BRITTO, LUIZ ROBERTO; FORLENZA, ORESTES VICENTE. Lithium and disease modification: A systematic review and meta-analysis in Alzheimer's and Parkinson's disease. AGEING RESEARCH REVIEWS, v. 95, p. 20-pg., 2024-02-24. (20/02109-3, 18/07366-4, 21/06378-1, 14/50873-3)

CORDEIRO, AUGUSTO MAGNO TRANQUEZI; SINGULANI, MONIQUE PATRICIO; TALIB, LEDA LEME; FORLENZA, ORESTES VICENTE. Down syndrome and Alzheimer's disease: Oxidative stress in the neurodegenerative process. JOURNAL OF ALZHEIMER'S DISEASE, v. N/A, p. 10-pg., 2025-04-03. (21/06378-1, 14/50873-3)

MORENO, MISLENE BISPO TEIXEIRA; SINGULANI, MONIQUE PATRICIO; VAN DE BILT, MARTINUS THEODORUS; LOCH, ALEXANDRE ANDRADE; GATTAZ, WAGNER FARID; TALIB, LEDA LEME. Cholesterol metabolism and its implications in psychotic disorders: a comparative study of individuals at ultra high risk and control groups. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. N/A, p. 8-pg., 2025-02-13. (21/06378-1, 14/50873-3)