Metformin: A Growing Journey from Glycemic Control to the Treatment of Alzheimer’s Disease and Depression

Abstract

: Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer’s disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders is not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways including AMPK, insulin and glucose transporters will be dissected and the potential therapeutic benefits of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

“…One of the characteristics of LOAD is the brain hypometabolism that is due to a decrease in glucose uptake. The drop in brain glucose levels is mainly related to a reduced glucose uptake associated with the decreased expression of glucose transporters in neurons, mainly GLUT1 and GLUT3 [ 56 ]. Therefore, it has been suggested that increasing glucose transport to neurons, for example with antidiabetic drugs such as metformin, may be a therapeutic approach in AD [ 56 ].…”

“…The drop in brain glucose levels is mainly related to a reduced glucose uptake associated with the decreased expression of glucose transporters in neurons, mainly GLUT1 and GLUT3 [ 56 ]. Therefore, it has been suggested that increasing glucose transport to neurons, for example with antidiabetic drugs such as metformin, may be a therapeutic approach in AD [ 56 ]. Likewise, alteration of different brain pathways associated with T2DM has been reported in LOAD patients.…”

“…Supporting this metabolic hypothesis of LOAD, a preclinical study with a neuron-specific human BACE1 knock-in mouse model (PLB4) conducted by Plucińska and colleagues demonstrated that the brain BACE1 overexpression by itself increased the risk of peripheral T2DM [ 56 ]. Therefore, this study suggested that LOAD progression can promote T2DM comorbidities in mice, independently of the classical obesogenic process, which could be a potential link between T2DM and LOAD.…”

Deciphering the Roles of Metformin in Alzheimer’s Disease: A Snapshot

“…However, a previous in vitro study showed that metformin alone exerted no significant effect on IDE but up-regulated AMPK-dependent BACE1 expression to increase Aβ generation in N2a695 cells overexpressing APP. A combination with insulin reversed the deleterious effect of metformin, suggesting an important regulatory role of insulin in metformin function ( Chen et al, 2009 ; El Massry et al, 2020 ). Similarly, overexpression of APP and PS1 in LAN5 neuroblastoma cells treated with metformin was suppressed by insulin.…”

Metformin attenuates sepsis-induced neuronal injury and cognitive impairment

“…A large body of literature has shown that the metformin was effective in regulating neurodegeneration because of its anti-apoptotic and antioxidant properties [ 15 , 16 ]. Metformin could potentially combat certain neurotoxins and malign effects of certain neurodegenerative diseases [ 17 , 18 ]. Therefore, we hypothesized that metformin has a certain therapeutic potential for cognitive impairment, and might alleviate sepsis-induced cognitive impairment.…”