Unveiling the mTOR pathway modulation by SGLT2 inhibitors: a novel approach to Alzheimer's disease in type 2 diabetes

Abstract

Alzheimer's disease (AD) is a neurological condition causing cognitive deterioration, leading to severe consequences. As the global prevalence of AD increases, new treatment approaches are needed to supplement current conventional therapies, as traditional treatments are not meeting the increasing demand for alternative treatments. It is increasingly evident that treating metabolic disorders like diabetes mellitus, obesity, and AD by blocking mechanistic target of rapamycin (mTOR) signalling is advantageous. Chronic mTOR activation may cause AD's metabolic, lysosomal, and mitochondrial dysfunction, tau hyperphosphorylation, amyloid plaque development, and disruption of the blood-brain barrier through endothelial cell malfunction. Chronic glucose loss through sodium-glucose transporter 2 (SGLT2) inhibitions can restore mTOR cycling, potentially halting or slowing AD pathogenesis. Chronic activation of mTOR is implicated in pathophysiological aspects of AD, such as metabolic dysfunction, tau hyperphosphorylation, amyloid plaque formation, and disruption of the blood-brain barrier. SGLT-2 inhibitors, commonly used in treating Type 2 Diabetes, have been shown to reduce mTOR activation and restore circadian regularity, a new finding in cognitive decline and metabolic disorders. Conversely, SGLT2 inhibitors decrease oxidative damage, inflammation, insulin signaling pathways, and proliferation of endothelial cells to enhance vascular tone, flexibility, and contractility. Along with reducing the formation of plaque containing amyloid and improving brain function, neural plasticity, acetylcholinesterase (AChE) activity, damage to the brain, and cognitive decline, they also regulate the mTOR pathway in the brain. Thus, repurposing SGLT-2 inhibitors, primarily used in diabetes treatment, presents a promising avenue for changing the way that AD is managed. The purpose of this review was to focus on the mTOR signalling cascade of SGLT 2 inhibitors to AD management in Type 2 Diabetes mellitus.

Keywords: Alzheimer’s disease; Diabetes mellitus; MTOR signalling futuristic therapeutics; SGLT inhibitors.