Aβ represents the key peptide in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder with a growing prevalence on a global scale. Although AD pathogenesis is not fully characterized yet, systemic accumulation of biomarkers of redox unbalance
(2) and inflammation,
(3) along with the deposition of insoluble proteinaceous aggregates in the brain, are hallmarks of disease progression.
(4−6)
....
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.
(12−15) Microglia can promote Aβ clearance through different mechanisms including the internalization and degradation of the peptide through the endosome/lysosome pathway
(16) and the secretion of enzymes able to degrade Aβ such as insulin-degrading enzyme (IDE),
(17,18) a major enzyme responsible for the degradation of insulin (Ins) and Aβ in vitro and in vivo.
(19−22) In fact, despite Ins being the preferred substrate for IDE, the enzyme also cleaves different amyloidogenic peptides such as amylin
(23) and Aβ.
(24,25) The latter,
(26,27) as well as IDE itself,
(28) 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.
