The insulin-degrading enzyme as a link between insulin and neuropeptides metabolism

Physiological Mechanisms Inherent to Diabetes Involved in the Development of Dementia: Alzheimer’s Disease

“…On the other hand, one of the mechanisms proposed to link insulin to cognitive impairment is its role in Aβ metabolism [ 111 , 115 ]. In this regard, insulin promotes the amyloidogenic pathway by modulating β and γ-secretases [ 114 , 141 , 142 ]. Additionally, insulin inhibits or hinders the passage of Aβ through the BBB [ 143 ].…”

Critical material designs for mucus- and mucosa-penetrating oral insulin nanoparticle development

“…The pH of the gastrointestinal tract, which ranges from extremely acidic (1.2–3.0) in the stomach to slightly basic (7.5–8.0) in the intestine, can cause pH-induced oxidation and deamination of insulin to alter its tertiary structure and therapeutic effect [28,29]. A plethora of enzymes exist in the gastrointestinal tract that can threaten the stability of insulin [30,31], including trypsin, α-chymotrypsin, and carboxypeptidases are found in the intestinal mucus [32]. Further, insulin is highly susceptible to degradation by the zinc metalloproteases found in abundance on intestinal brush border membrane surfaces [32].…”

Neuroprotective Effect of Carnosine Is Mediated by Insulin-Degrading Enzyme

“…Both peripheral macrophages and microglia, the brain-resident immune cells, represent two different specialized cell types activated during the immune response. , There is a bidirectional cross-talk between microglia and neurons; in fact, neurons inform microglia regarding their status and control activation and the motility of microglia, while microglial cells are able to modulate neuronal homeostasis . Reactive microglia co-localize with Aβ within the neuritic plaques observed in the brain of AD subjects and could be implicated either in the removal or, paradoxically, in the formation of amyloid plaques. − Microglia can promote Aβ clearance through different mechanisms including the internalization and degradation of the peptide through the endosome/lysosome pathway and the secretion of enzymes able to degrade Aβ such as insulin-degrading enzyme (IDE), , a major enzyme responsible for the degradation of insulin (Ins) and Aβ in vitro and in vivo. − In fact, despite Ins being the preferred substrate for IDE, the enzyme also cleaves different amyloidogenic peptides such as amylin and Aβ. , The latter, , as well as IDE itself, represents a well-recognized neurobiological link and a common pharmacological target between AD and type 2 diabetes (T2DM). Mice with the homozygous deletion of the IDE gene (IDE –/− ) and an IDE deficiency show increased cerebral accumulation of endogenous Aβ, as well as hyperinsulinemia and glucose intolerance, hallmarks of T2DM .…”

“…Positive allosteric modulators of the activity of IDE are currently studied as potential drugs for both pathologies, as shown by the use of a novel IDE inhibitor in a mouse model of T2DM, while activators of IDE have been considered for AD treatment . In addition, IDE has been recognized to be involved in many other biochemical pathways wherein it does not play a proteolytic action but rather a regulatory one, ,− envisaging a multifaceted role of this enzyme within the dynamics of metabolism of living organisms.…”