Abstract
Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60–70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. New insights into the pathogenesis of AD are needed in order to develop novel pharmacologic approaches. In recent years, numerous studies have shown that insulin resistance plays a significant role in the development of AD. Over 80% of patients with AD have type II diabetes (T2DM) or abnormal serum glucose, suggesting that the pathogenic mechanisms of insulin resistance and AD likely overlap. Insulin resistance increases neuroinflammation, which promotes both amyloid β-protein deposition and aberrant tau phosphorylation. By increasing production of reactive oxygen species, insulin resistance triggers amyloid β-protein accumulation. Oxidative stress associated with insulin resistance also dysregulates glycogen synthase kinase 3-β (GSK-3β), which leads to increased tau phosphorylation. Both insulin and amyloid β-protein are metabolized by insulin degrading enzyme (IDE). Defects in this enzyme are the basis for a strong association between T2DM and AD. This review highlights multiple pathogenic mechanisms induced by insulin resistance that are implicated in AD. Several pharmacologic approaches to AD associated with insulin resistance are presented.
Highlights
Alzheimer disease (AD) is a chronic degenerative brain disease characterized by memory loss, cognitive impairment, and loss of activities of daily living (Jha et al, 2019)
Binding of advanced glycation end products (AGEs) to their cellular receptors (RAGE) upregulates glycogen synthase kinase 3β (GSK-3β), causing tau hyperphosphorylation (Peng et al, 2007; Li et al, 2012a,b), and activates the NF-κB pathway, which produces reactive oxygen species (ROS) and pro-inflammatory cytokines [interleukin (IL)-6, IL-1β, TNF] (Kandimalla et al, 2017). These cytokines are observed to increase accumulation of amyloid β-protein in AD by two mechanisms: (1) increased levels of proinflammatory cytokines inhibit phagocytosis of amyloid β-protein in AD brains thereby hindering the removal of plaque by resident microglia; (2) TNF has been shown to upregulate the production of amyloid β-protein via activation of the c-Jun N-terminal kinase (JNK)-dependent mitogen-activated protein kinase (MAPK) pathway, which promotes phosphorylation and cleavage of amyloid precursor protein (APP) (Liaoi et al, 2004; McAlpine and Tansey, 2008; Colombo et al, 2009; Montgomery et al, 2011; Cheng et al, 2014; Ahn et al, 2016; Decourt et al, 2017; Zhang et al, 2019)
Apart from amyloid targets, in 2020, according to the Food and Drug Administration (FDA) registry, there were over 50 agents in clinical trials targeting tau protein, inflammation and metabolism (Cummings et al, 2020)
Summary
Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience. Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60–70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. Insulin resistance increases neuroinflammation, which promotes both amyloid β-protein deposition and aberrant tau phosphorylation. Oxidative stress associated with insulin resistance dysregulates glycogen synthase kinase 3-β (GSK-3β), which leads to increased tau phosphorylation. Both insulin and amyloid β-protein are metabolized by insulin degrading enzyme (IDE). Several pharmacologic approaches to AD associated with insulin resistance are presented
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