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.
Highlights
Sporadic Alzheimer’s disease (AD) is the major form of cognitive impairment and dementia (Chakrabarti et al, 2015; Jagust, 2018)
Insulin resistance was shown to be implicated in AD pathogenesis and diminished insulin signaling have been detected in the brains of AD patients (Talbot et al, 2012; Ekblad et al, 2018)
This study demonstrated the favorable effect of the modulation of gut microbiota and attenuation of insulin resistance via probiotics fermentation technology (PFT) in ameliorating various pathological mechanisms that underlie the pathogenesis of AD with consequent improvement in cognition
Summary
Sporadic Alzheimer’s disease (AD) is the major form of cognitive impairment and dementia (Chakrabarti et al, 2015; Jagust, 2018). Insulin resistance was shown to be implicated in AD pathogenesis and diminished insulin signaling have been detected in the brains of AD patients (Talbot et al, 2012; Ekblad et al, 2018) In this context, insulin resistance was revealed to promote Aβ secretion and to halt its clearance by decreasing the production of insulin degrading enzyme (IDE), a key enzyme for Aβ degradation, and competing with Aβ for IDE (Zhao et al, 2004; Gabbouj et al, 2019). Insulin resistance was revealed to promote Aβ secretion and to halt its clearance by decreasing the production of insulin degrading enzyme (IDE), a key enzyme for Aβ degradation, and competing with Aβ for IDE (Zhao et al, 2004; Gabbouj et al, 2019) It results in mitochondrial dysfunction with consequent oxidative stress and elevation of advanced glycation end-products (AGE), which are all implicated in AD development (Butterfield et al, 2014). Insulin resistance in metabolic syndrome underlies several pathological processes involved in AD development
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