Evaluation of the omega-3's molecular mechanism of action in the early-onset of Alzheimer Disease associated to obesity and type 2 Diabetes in mice: the role GPR120

• Grant number: 19/13210-0
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2021
• End date: January 31, 2024
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Dennys Esper Corrêa Cintra
• Grantee: Dennys Esper Corrêa Cintra
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Associated researchers: Adelino Sanchez Ramos da Silva ; Eduardo Rochete Ropelle ; José Rodrigo Pauli ; Leandro Pereira de Moura ; Marcella Ramos Sant'Ana ; Marcio Luiz Figueredo Balthazar ; Rodrigo Ramos Catharino

Abstract

Obesity advances worldwide in an uncontrolled way, being considered a predisposing factor also to neurodegenerative diseases such as Alzheimer's Disease (AD). Not only the senescence is involved in the pathogenesis of AD, but also the inflammatory process characteristic of the obesogenesis, which can anticipate its onset and even be an initial trigger. Hippocampal neuroinflammation can precipitate neurodegeneration, leading to irreversible damage to memory. Diets rich in saturated fats can disrupt hippocampal homeostatic neural circuits, formed by complex circuitry among glial cells, neurons, oligodendrocytes and astrocytes. In this neuronal group, Toll-type receptors (TLR) mediate the inflammatory effects of fats, and, cytokine receptors, intensify inflammation. Consequently, inflammasomal activation, dysregulation of the endoplasmic reticulum, and autophagy failure induce apoptosis. Side-by-side inflammation, hippocampal insulin resistance can reduce the local clearance of beta-amyloid protein (²A), inducing protein tangles harmful to synapses, and hyperphosphorylates the TAU protein, which disrupts the neuronal cytoskeleton and intensifies the signs of death. Together, these phenomena imply the advancement of AD, followed by serious clinical outcomes, such as memory loss and dementia. On the other hand, omega-3 (É3) unsaturated fatty acids are known to be potent anti-inflammatory agents, and their consumption correlates with benefits for AD patients. However, this proposal does not yet find robust mechanistic support. The É3 is GPR120 receptor agonist, which seems to disrupt the intracellular signaling controlled by the TLR4, TNF± and IL1² receptors and by the inflammasome. However, its presence and function has not been demonstrated in the hippocampus. Synthetic GPR120 agonists have been developed due to wide therapeutic possibilities, already under investigation on clinical trials. If plausible, this mechanism opens new pharmacological possibilities for postponement of AD, however, the É3 is found in food, and it would also become feasible and, mainly, of access to the entire population. (AU)

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)

RODRIGUES, PATRICIA BRITO; DATILO, MARCELLA NEVES; SANT'ANA, MARCELLA RAMOS; NOGUEIRA, GUILHERME AUGUSTO DA SILVA; MARIN, RODRIGO MIGUEL; NAKANDAKARI, SUSANA CASTELO BRANCO RAMOS; DE MOURA, LEANDRO PEREIRA; SILVA, ADELINO SANCHEZ RAMOS DA; ROPELLE, EDUARDO ROCHETE; PAULI, JOSE RODRIGO; et al. The early impact of diets enriched with saturated and unsaturated fatty acids on intestinal inflammation and tight junctions. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 119, p. 12-pg., 2023-09-01. (12/07129-6, 19/13168-3, 19/13210-0)

BATISTA, ELLENCRISTINA DA SILVA; BRANCO RAMOS NAKANDAKARI, SUSANA CASTELO; RAMOS DA SILVA, ADELINO SANCHEZ; PAULI, JOSE RODRIGO; DE MOURA, LEANDRO PEREIRA; ROPELLE, EDUARDO ROCHETE; CAMARGO, ENILTON A.; CINTRA, DENNYS ESPER. Omega-3 pleiad: The multipoint anti-inflammatory strategy. CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION, v. N/A, p. 16-pg., 2022-11-10. (20/13443-1, 19/13210-0, 19/13168-3)

NAKANDAKARI, SUSANA CASTELO BRANCO RAMOS; GASPAR, RAFAEL CALAIS; KUGA, GABRIEL KEINE; RAMOS, CAMILA DE OLIVEIRA; VIEIRA, RENAN FUDOLI; RIOS, THAIANE DA SILVA; MUNOZ, VITOR ROSETTO; SANT'ANA, MARCELLA RAMOS; SIMABUCO, FERNANDO MOREIRA; SILVA, ADELINO SANCHEZ RAMOS DA; et al. Short-term flaxseed oil, rich in omega 3, protects mice against metabolic damage caused by high-fat diet, but not inflammation. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 114, p. 11-pg., 2023-02-11. (19/13168-3, 19/13210-0)