Cross-Interplay between Osmolytes and mTOR in Alzheimer's Disease Pathogenesis

Abstract

: 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.

The landscape of metabolic brain alterations in Alzheimer’s disease

“…Osmolytes are a class of molecules that primarily sustain cell integrity (56). They have been suggested to play a neuroprotective role in AD by activating mTOR-independent autophagy signaling to inhibit the accumulation of aggregated proteins(57). Osmolytes also affect protein folding (58), and their therapeutic potential has been discussed in AD as well as other neurodegenerative proteinopathies (59).…”

“…Of these processes, metabolic alterations of osmoregulation within the central nervous system have, to the best of our knowledge, so far not been studied in detail. Osmolytes participate in multiple critical processes associated with neurogenerative diseases including protein folding 63 , autophagy 50 , and hyperexcitation of neurons 49 . While our observations might to some extent be confounded by, e.g., systematic differences in the hydration status of AD patients prior to death, the large number and strong significance of associations within this class suggests a potentially functional link to pathomechanisms in AD.…”

Urine metabolic phenotyping in children with nocturnal enuresis and comorbid neurobehavioral disorders

“…The deficiencies had a close linkage of modifications in histone and DNA methylation in brain 38 , 39 . Furthermore, the influence of osmolyte homeostasis on neural communication has been studied in many literatures 40 – 42 . Knight and his colleagues demonstrated a prominent role of brain betaine in neurotransmission 43 .…”

The landscape of metabolic brain alterations in Alzheimer's disease

“…54 They have been suggested to play a neuroprotective role in AD by activating mammalian target of rapamycin-independent autophagy signaling to inhibit the accumulation of aggregated proteins. 55 Osmolytes also affect protein folding, 56 and their therapeutic potential has been discussed in AD as well as other neurodegenerative proteinopathies. 57 Moreover, osmolyte imbalances can impact neuronal hyperexcitation by influencing neurotransmitter uptake.…”

“…84 Further, we observed numerous osmolytes being highly associated with AD, which suggests a potential functional link with the pathomechanisms of the disease. Osmolytes participate in multiple critical processes associated with neurogenerative diseases, including protein folding, 85 autophagy, 55 and hyperexcitation of neurons. 54 While our observations on osmolytes might to some extent be confounded by, for example, systematic differences in the hydration status of AD patients before death, to the best of our knowledge, these alterations within the central nervous system have so far not been studied in detail.…”