Peripheral and central effects of dexibuprofen on APP/PS1 mice fed with an obesogenic diet

Abstract

Although aging is the major risk for Alzheimer's disease (AD), other additional risk factors contribute to the development of AD such as diabetes mellitus (DM). The identification of molecular pathways to this neurological disorder is important to find a treatment. The neuroinflammatory hypothesis presumes that AD may be considered as a chronic brain inflammatory process. APP/PS1 transgenic mice fed with a high fat diet (HFD) were non-treated (APP/PS1) or treated (APP/PS1 DXI) with water supplemented with 20 mg/kg/day DXI for 3 months before being sacrificed. As expected, the intake of HFD produced a significant increase in weight in APP/PS1 HFD compared to APP/PS1 mice (**p <0.01). Conversely, there was a significant decrease in weight in the group APP/PS1 HFD DXI versus APP/PS1 HFD (*p <0.05). In the intraperitoneal glucose tolerance test (IP-GTT), HFD administration resulted in a significant increase in blood glucose levels in APP/PS1 HFD versus APP/PS1 mice (** p <0.01). There was a significant decrease in blood glucose levels in the group APP/PS1 HFD DXI versus APP/PS1 HFD (* p <0.05). Regarding to the intraperitoneal insulin tolerance test (IP-ITT), HFD administration ensured a significant increase in blood glucose levels in APP/PS1 HFD versus APP/PS1 mice (** p <0.01). DXI-treatment showed a significant decrease in blood glucose plasma level between APP/PS1 HFD versus APP/PS1 HFD DXI (** p <0.01).

In Morris water maze and object recognition tests, APP/PS1 HFD mice showed an increased memory decline compared to wild type (WT) mice which was improved after DXI treatment. As expected, APP/PS1 DXI mice showed a significant decrease in the amount of b-amyloid plaques in cortex compared to non-treated animals. Likewise, several proteins involved in memory processes, insulin pathways, neuroinflammation showed a significant improved in DXI treated animals but no in APP/PS1 HFD mice.

In conclusion, our research suggest that DXI improve central and peripheral parameters in a mixed model of DM and AD, so that the inflammatory process could be a link between both diseases. DXI could be a suitable coadyuvant drug for the prevention of cognitive loss in AD through the improvement of pathways related to the neuroinflammatory process.