Lima-Filho Ricardo A S, Benedet Andréa L, De Bastiani Marco Antônio, Povala Guilherme, Cozachenco Danielle, Ferreira Sergio T, De Felice Fernanda G, Rosa-Neto Pedro, Zimmer Eduardo R, Lourenco Mychael V
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, 413 45, Sweden.
Brain Commun. 2023 Aug 17;5(4):fcad216. doi: 10.1093/braincomms/fcad216. eCollection 2023.
Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-β deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-β PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-β, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.
含III型纤连蛋白结构域蛋白5（FNDC5）及其衍生激素鸢尾素与人类的代谢控制有关，已报道的FNDC5单核苷酸多态性与肥胖和代谢综合征相关。在患有阿尔茨海默病所致痴呆的受试者中，脑内FNDC5/鸢尾素水平降低。由于脑葡萄糖代谢受损在衰老过程中出现，且在阿尔茨海默病中较为突出，因此，我们在阿尔茨海默病神经影像倡议组织的240名认知未受损和485名认知受损老年个体队列中，研究了FNDC5基因单核苷酸多态性（rs1746661）与脑葡萄糖代谢及淀粉样β蛋白沉积的关联。在携带FNDC5 rs1746661（T）等位基因的认知未受损老年个体中，我们观察到与记忆相关脑区低葡萄糖代谢的区域减少，且脑淀粉样β蛋白PET负荷增加。在FNDC5 rs1746661（T）等位基因携带者和非携带者之间，未观察到认知或脑脊液淀粉样β蛋白、磷酸化tau蛋白和总tau蛋白水平的差异。我们的结果表明，FNDC5的一种基因变异与老年个体脑葡萄糖代谢降低有关，并提示FNDC5可能参与易受阿尔茨海默病病理生理影响的脑区的脑代谢调节。了解代谢相关基因的基因变异与脑代谢特征之间的关联，可能有助于阐明人类脑代谢的遗传调节因子。
