Projeto FAPESP - 2019-13210-0

Obesity is a predisposing condition to several diseases with metabolic relation, widely explored in clinical trials or basic sciences. Thus, neurodegenerative diseases have been associated with body weight gain. Interestingly, Alzheimer's Disease (AD) has always been strongly correlated to the aging process; however, recent studies have shown that the obesogenic process interferes with the early onset AD characteristics. The chronic and low-grade inflammatory process inherent to obesity appears to participate in AD, once the neuroinflammation in
hippocampal regions would activate a pro-degenerative signaling. Diets rich in saturated fatty acids seem to turn unstable the hippocampal neural homeostatic circuits. Cell types such as glia, oligodendrocytes, astrocytes, etc. control these circuits, and the Toll-like receptors mediate inflammatory signaling induced by nutrients in the central nervous system, parallel to cytokines and the intracellular inflammasome structure. The inflammation progression can activate the endoplasmic reticulum stress, autophagy, and apoptosis. The neuronal death represents a severe outcome per se, in which AD culminates with loss of memory and dementia. In addition, the hippocampal insulin resistance seems to decrease beta-amyloid (Aβ) protein clearance, inducing oligomerization and senile plate formation. It is a consequence of TAU hyperphosphorylation, which
increases Aβ deposition; and damages the neuronal cytoskeleton, decreasing the cellular signal transduction, followed by neuronal cell death. Unsaturated fatty acids such as omega 3 (ω3) are recognized as potent anti-inflammatory agents, with their consumption associated with benefits from AD patients. However, this observation is not mechanistically robustly supported. The ω3 fatty acids is a GPCR receptor (GPR120) agonist, which disrupts the signaling controlled by TLR4, TNFα and IL1β receptors. Nevertheless, the presence and function of GPR120 in the hippocampus was not shown. Several synthetic GPR120 agonists have been developed, due to their therapeutic possibilities. If the plausibility of these mechanisms were proved, the pharmacological possibilities to delay AD could be projected. However, with ω3 fatty acid easily found in nature, intrinsic to foods, it would be possible to be accessed by all populations.