Therapeutic Efficacy of the Inositol D-Pinitol as a Multi-Faceted Disease Modifier in the 5×FAD Humanized Mouse Model of Alzheimer’s Amyloidosis

Abstract

Background. Objectives, Alzheimers disease (AD), a leading cause of dementia, lacks effective long term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Abeta) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential. Methods, this study suggests dPinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg kg day) could reverse the AD like disease progression in the 5XFAD mice. Results, results showed that treatment of 5XFAD mice with DPIN improved cognition, reduced hippocampal Abeta and hyperphosphorylated tau levels, increased insulin degrading enzyme (IDE) expression, enhanced procognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the proinflammatory impact of the leaky gut observed in 5XFAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS associated inflammation, as well as restored intestinal proteins such as Claudin3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition. Conclusions, these findings underscore DPINs promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier.