: Alzheimer's Disease, characterized by the accumulation of amyloid-β (Aβ), hyperphosphorylated tau, PHFs, NFTs, and mTOR hyperactivity, is a neurodegenerative disorder affecting people across the globe. Osmolytes are small, compatible organic molecules that not only osmoregulate but also cytoprotective through their role in folding function and stability of proteins, preventing proteins aggregation, and counteracting effects of denaturing solutes on proteins. Osmolytes such as sorbitol, inositol, and betaine play an important role in maintaining homeostasis during hyperosmotic stress. The selective advantage of utilizing osmolytes over inorganic ions by cells is in maintaining cell volume without compromising cell function, which is important for organs such as the brain. Osmolytes have been documented both as neuroprotector as well as to have neurodegenerative effects. Betaine, sucrose and trehalose supplementation has been seen to induce autophagy thereby inhibiting the accumulation of Aβ. In contrast, sucrose has also been associated with mTOR hyperactivity, a hallmark of AD pathology. The neuroprotective action of taurine is revealed when taurine supplementation is seen to inhibit neural damage, apoptosis and oxidative damage. Inositol stereoisomer’s namely, scylloinositol and Myo-inositol, have also been seen to inhibit Aβ production and plaque accumulation in the brain, inhibiting AD pathogenesis. However, TMAO affects the aging process adversely by de-regulating the mTOR signalling pathway and then inducing cognitive dysfunction via degradation of chemical synapses and synaptic plasticity. Thus it can be concluded that osmolytes may act as a potential therapeutic approach for neurodevelopmental disorders. In this review, we have focussed upon the impact of osmolytes on mTOR signalling pathway and thereby its role in AD pathogenesis.

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Dialysis-related amyloidosis (DRA) is considered an inescapable consequence of renal failure. Upon prolonged hemodialysis, it involves accumulation of toxic β2-microglobulin (β2m) amyloids in bones and joints. Current treatment methods are plagued with high cost, low specificity, and low capacity. Through our in vitro and in cellulo studies, we introduce a peptidomimetic-based approach to help develop future therapeutics against DRA. Our study reports the ability of a nontoxic, core-modified, bispidine peptidomimetic analogue “B­(LVI)2” to inhibit acid-induced amyloid fibrillation of β2m (Hβ2m). Using thioflavin-T, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and transmission electron microscopy analysis, we demonstrate that B­(LVI)2 delays aggregation lag time of Hβ2m amyloid fibrillation and reduces the yield of Hβ2m amyloid fibrils in a dose-dependent manner. Our findings suggest a B­(LVI)2-orchestrated alteration in the route of Hβ2m amyloid fibrillation resulting in the formation of noncytotoxic, morphologically distinct amyloid-like species. Circular dichroism data show gradual sequestration of Hβ2m species in a soluble nonamyloidogenic noncytotoxic conformation in the presence of B­(LVI)2. Dynamic light scattering measurements indicate incompetence of Hβ2m species in the presence of B­(LVI)2 to undergo amyloid-competent intermolecular associations. Overall, our study reports the antifibrillation property of a novel peptidomimetic with the potential to bring a paradigm shift in therapeutic approaches against DRA.