O papel do mGluR5 na expressão de proteínas envolvidas na poda sináptica em um modelo murino da doença de Alzheimer

Abstract

Alzheimer's disease (AD) is the major cause of dementia. The etiology of AD is not fully understood. Most of the cases are of unknown origin. Increasing evidence demonstrates the relevance of immunological mechanisms in AD pathology. Recent data shows that the synaptic loss observed since early stages of AD is due to increased synaptic pruning mediated by C1q and C3, proteins of the complement system, which mark synapses for phagocytosis by microglia. The chemokine CX3CL1 plays a central role in the regulation of microglial activities and there are indications of its participation in the synaptic pruning process. Synaptic loss is the strongest correlate with the cognitive deficits found in AD. The amyloid-β peptide (Aβ), central in the pathology of AD, interacts with the metabotropic glutamate receptor 5 (mGluR5), altering its intracellular signalling pathways and initiating the dysfunctions in synaptic activities. Therefore, the aim of this work was to investigate the role of mGluR5 in the expression of proteins involved in the synaptic pruning. Thereunto, we used male and female WT and knockout mGluR5 (mGluR5-/-) mice submitted to intracerebroventricular injection of Aβ 1-42 or PBS. Our results demonstrated that the injection of Aβ 1-42 and the mGluR5 -/- were not able to induce an increase in the microglia number in the hippocampus of male mice, although it appears that the morphology of these cells shows an activation profile. In addition, injection of Aβ1-42 and mGluR5-/- did not induce changes in the levels of C3 and CX3CL1 mRNAs in male mice. In contrast, it was observed an elevation of C3 mRNA levels in the hippocampus of female mGluR5 -/- mice injected with PBS. At protein level, our results demonstrated a decrease in CX3CL1 only in the hippocampus of mGluR5 -/- female mice injected with Aβ 1-42 compared to female WT mice injected with PBS. More experiments are needed to investigate the mechanisms underlying synaptic loss in AD, which appear to be distinct in males and females. The present work emphasizes the importance of the use of models of both sexes in scientific research, given the considerable interference of estrogens and androgens in the physiological mechanisms. The use of males and females is even more important in contexts such as AD, where researches performed in males are still the majority, despite the higher AD incidence in females, which tarnishes the extrapolation of the data to the human population.