Enhancement of Insulin/PI3K/Akt Signaling Pathway and Modulation of Gut Microbiome by Probiotics Fermentation Technology, a Kefir Grain Product, in Sporadic Alzheimer’s Disease Model in Mice

Abstract

Sporadic Alzheimer’s disease (AD) is the most common neurodegenerative disorder with cognitive dysfunction. Remarkably, alteration in the gut microbiome and resultant insulin resistance has been shown to be connected to metabolic syndrome, the crucial risk factor for AD, and also to be implicated in AD pathogenesis. Thus, this study, we assessed the efficiency of probiotics fermentation technology (PFT), a kefir product, in enhancing insulin signaling via modulation of gut microbiota to halt the development of AD. We also compared its effectiveness to that of pioglitazone, an insulin sensitizer that has been confirmed to substantially treat AD. AD was induced in mice by a single injection of intracerebroventricular streptozotocin (STZ; 3 mg/kg). PFT (100, 200, 400 mg/kg) and pioglitazone (30 mg/kg) were administered orally for 3 weeks. Behavioral tests were conducted to assess cognitive function, and hippocampal levels of acetylcholine (Ach) and β-amyloid (Aβ1–42) protein were assessed along with histological examination. Moreover, the expression of the insulin receptor, insulin degrading enzyme (IDE), and the phosphorylated forms of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), mammalian target of rapamycin (mTOR), and tau were detected. Furthermore, oxidative stress and inflammatory biomarkers were estimated. Treatment with PFT reversed STZ-induced neurodegeneration and cognitive impairment, enhanced hippocampal Ach levels, and reduced Aβ1–42 levels after restoration of IDE activity. PFT also improved insulin signaling, as evidenced by upregulation of insulin receptor expression and activation of PI3K/Akt signaling with subsequent suppression of GSK-3β and mTOR signaling, which result in the downregulation of hyperphosphorylated tau. Moreover, PFT significantly diminished oxidative stress and inflammation induced by STZ. These potential effects were parallel to those produced by pioglitazone. Therefore, PFT targets multiple mechanisms incorporated in the pathogenesis of AD and hence might be a beneficial therapy for AD.

Potential mechanisms underlying the association between type II diabetes mellitus and cognitive dysfunction in rats: a link between miRNA-21 and Resveratrol’s neuroprotective action

“…This state of brain insulin resistance may be the cause of memory loss in diabetic rats. This was in agreement with several studies that have reported memory disturbances in cases of disturbed brain insulin signaling (El Sayed et al 2021 ). Different studies and clinical trials have shown that resveratrol treatment notably lowers blood glucose levels and improves insulin action in type 2 diabetic patients.…”

Probiotic Bifidobacterium breve MCC1274 Mitigates Alzheimer’s Disease-Related Pathologies in Wild-Type Mice

“…However, the underlying mechanism by which B. breve MCC1274 supplementation activates Akt is still unclear. Several studies have demonstrated that some probiotics elevate Akt phosphorylation [58,59]. However, further investigations are required to understand the mechanism of B. breve MCC1274-mediated activation of the Akt-GSK-3β pathway.…”

Naringin Protects against Tau Hyperphosphorylation in Aβ25–35-Injured PC12 Cells through Modulation of ER, PI3K/AKT, and GSK-3β Signaling Pathways

“…To examine learning and memory, we performed the novel object recognition (NOR) test [ 16 ]. The test is based on animals' innate preference for a novel object, in which mice remembering the familiar object will devote more time exploring a novel one [ 17 ]. Each mouse was placed in a box (without objects) for 5 minutes to adapt to the surroundings (habituation).…”