Zamarbide Marta, Martinez-Pinilla Eva, Gil-Bea Francisco, Yanagisawa Masashi, Franco Rafael, Perez-Mediavilla Alberto
Neuroscience Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain.
Int J Mol Sci. 2022 Mar 24;23(7):3533. doi: 10.3390/ijms23073533.
The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APP mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R/APP, to perform cognition studies and to assess, by immunoblotting Aβ and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R/APP mice do not have the characteristic memory impairment of 12-month-old APP mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer's disease (AD)-related features, such as amyloid beta (Aβ) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3β and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks.
游离脂肪酸FFA3受体（FFA3R）属于G蛋白偶联受体（GPCR）超家族。在肠道和脂肪组织中，它参与能量代谢的调节，但其在大脑中的功能尚不清楚。我们的目标，首先是研究该受体在阿尔茨海默病（AD）患者不同疾病阶段海马体中的表达，其次是评估Ffar3基因的基因失活是否会影响APP小鼠模型的表型特征。通过RT-qPCR分析了死后人类海马体样本以及野生型和转基因小鼠海马体中FFA受体转录本的表达。我们构建了双转基因小鼠FFA3R/APP，以进行认知研究，并通过免疫印迹评估Aβ和tau病理以及突触可塑性相关蛋白的差异表达。首次证明了FFA3R在人类海马体中的存在及其过表达，即使在AD的早期阶段也是如此。值得注意的是，FFA3R/APP小鼠没有12月龄APP小鼠的特征性记忆障碍。此外，这个新构建的转基因品系不会出现最重要的阿尔茨海默病（AD）相关特征，如淀粉样β蛋白（Aβ）在大脑中的积累和tau过度磷酸化。这些发现伴随着胰岛素降解酶（IDE）水平的升高以及tau激酶GSK3β和Cdk5活性的降低。我们得出结论，大脑中的FFA3R参与认知过程，其失活可防止类似AD的认知衰退和病理特征。
