Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APPswe Alzheimer’s Disease Mouse Model

Abstract

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 APPswe 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−/−/APPswe, 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−/−/APPswe mice do not have the characteristic memory impairment of 12-month-old APPswe 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.

The Cognitive Improvement and Alleviation of Brain Hypermetabolism Caused by FFAR3 Ablation in Tg2576 Mice Is Persistent under Diet-Induced Obesity

“…A recent study has already demonstrated that genetic inactivation of FFAR3 reverses the cognitive impairment showed by Tg2576 mice [ 51 ]. However, that study tested the mice at the age of 12 months, i.e., the age when the characteristic cognitive impairment present in Tg2576 begins to be manifested.…”

“…Notably, a previous study addressing the role of FFAR3 in AD showed that Tg-FFAR3 −/− mice showed a significant decrease in amyloid plaque burden [ 51 ]. As described in that study, cortical homogenates obtained from 12-month-old Tg-FFA3R −/− mice showed barely detectable levels of Aβ 42 measured by ELISA, as well as a completely absence of Aβ deposits assessed by immunohistochemical analysis in hippocampal and frontal cortex sections of Tg-FFA3R −/− mice.…”

“…Concerning SCFA receptors, in contrast to the expression observed in gut and peripheral organs, most studies have found a very low expression level of FFAR3 in the brain [ 44 , 71 , 101 ]. However, it has been recently demonstrated that FFARs are differentially expressed in the hippocampus of control subjects’ and AD patients’ brains [ 51 ]. In that study, Zamarbide et al showed that FFAR3 mRNA levels are increased, while FFAR1 and FFAR2 appeared to be downregulated in early stages of the AD pathology, reasoning that FFAR3 could play a key role in AD onset and progression.…”

“…Nonetheless, regarding the nervous system, FFAR3 has been confirmed as the mediator of the effects exerted by SCFAs on sympathetic nervous system activity, therefore participating in the control of systemic energy homeostasis [ 50 ]. Crucially, the hippocampal expression of both FFAR2 and FFAR3 was recently identified, and a striking 5-fold upregulation of FFAR3, but not FFAR2, expression was identified in initial stages of AD [ 51 ]. Additionally, the same study demonstrated that the loss of FFAR3 is sufficient to reverse the cognitive impairment and amyloid-β (Aβ) pathology exhibited by the Tg2576 AD mouse model, which overexpresses the amyloid precursor protein (APP) carrying the Swedish mutation [ 51 ].…”

“…Crucially, the hippocampal expression of both FFAR2 and FFAR3 was recently identified, and a striking 5-fold upregulation of FFAR3, but not FFAR2, expression was identified in initial stages of AD [ 51 ]. Additionally, the same study demonstrated that the loss of FFAR3 is sufficient to reverse the cognitive impairment and amyloid-β (Aβ) pathology exhibited by the Tg2576 AD mouse model, which overexpresses the amyloid precursor protein (APP) carrying the Swedish mutation [ 51 ].…”