Abstract
IntroductionRigorous research in the last few years has shown that in addition to the classical mechanism of neurodegeneration, certain unconventional mechanisms may also lead to neurodegenerative disease. One of them is a widely studied metabolic disorder: type 2 diabetes mellitus (T2DM). We now have a clear understanding of glucose‐mediated neurodegeneration, mostly from studies in Alzheimer's disease (AD) models. AD is recognized to be significantly associated with hyperglycemia, even earning the term “type 3 diabetes.” Here, we review first the pathophysiology of AD, both from the perspective of classical protein accumulation, as well as the newer T2DM‐dependent mechanisms supported by findings from patients with T2DM. Secondly, we review the different pathways through which neurodegeneration is aggravated in hyperglycemic conditions taking AD as a case study. Finally, some of the current advances in AD management as a result of recent research developments in metabolic disorders‐driven neurodegeneration are also discussed.MethodsRelevant literatures found from PubMed search were reviewed.ResultsApart from the known causes of AD, type 2 diabetes opens a new window to the AD pathology in several ways. It is a bidirectional interaction, of which, the molecular and signaling mechanisms are recently studied. This is our attempt to connect all of them to draw a complete mechanistic explanation for the neurodegeneration in T2DM. Refer to Figure 3.ConclusionThe perspective of AD as a classical neurodegenerative disease is changing, and it is now being looked at from a zoomed‐out perspective. The correlation between T2DM and AD is something observed and studied extensively. It is promising to know that there are certain advances in AD management following these studies.
Highlights
Rigorous research in the last few years has shown that in addition to the classical mechanism of neurodegeneration, certain unconventional mechanisms may lead to neurodegenerative disease
It is essential to focus research on the relationship between metabolic disorders and neuronal alterations resulting from such disorders, in order to unravel the molecular mechanisms behind it (Calvo-Ochoa & Arias, 2015)
We provide a concise review of diabetes-associated mechanisms of neurodegeneration and cognitive impairment, with an emphasis on the pathophysiology of Alzheimer's disease (AD)
Summary
Neurodegenerative diseases are generally characterized by cellular accumulation of misfolded proteins, ROS production due to mitochondrial dysfunction, and disruption of the autophagy machinery in neuronal cells. This implies that in patients with AD, impaired cerebral insulin signaling due to neuroinflammation may be a possible link between cerebral dysfunction and T2DM (Ferreira et al, 2014; Mehla et al, 2014; Nasoohi et al, 2018) Another mechanism by which hyperglycemia-induced neuroinflammatory pathways may affect the brain is through Toll-like receptor 4 (TLR4). In vitro and in vivo studies using diabetic mouse models have reported that metformin treatment improves autophagic clearance of hyperphosphorylated tau protein in patients with AD (Chen et al, 2019) This is a promising step toward the generation of effective therapeutics targeting neurodegeneration in both AD and T2DM-associated early-AD patients. FDA approved drug for hypertension and in phase III clinical trial (NCT00274118) for T2DM and in phase III clinical trial for AD (NCT00274118) (Cummings, Lee, Ritter, & Zhong, 2018)
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