Mechanisms Underlying Insulin Deficiency-Induced Acceleration of β-Amyloidosis in a Mouse Model of Alzheimer's Disease

摘要: Although evidence is accumulating that diabetes mellitus an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to acceleration of AD progression remain unclear. In this study, we applied streptozotocin (STZ) induce experimental transgenic mice (5XFAD model) and investigated how deficiency affects β-amyloidogenic processing amyloid precursor protein (APP). Two half months after 5XFAD were treated with STZ (90 mg/kg, i.p., once daily two consecutive days), they showed significant reductions brain levels without changes receptor expression. Concentrations cerebral amyloid-β peptides (Aβ40 Aβ42) significantly increased STZ-treated as compared vehicle-treated controls. Importantly, STZ-induced upregulated both β-site APP cleaving enzyme 1 (BACE1) full-length mouse brains, was accompanied dramatic elevations β-cleaved C-terminal fragment (C99). Interestingly, BACE1 mRNA not affected, whereas phosphorylation translation initiation eIF2α, a mechanism proposed mediate post-transcriptional upregulation BACE1, elevated mice. Meanwhile, GGA3, adapter responsible sorting lysosomal degradation, are indistinguishable between STZ- Moreover, treatments did affect Aβ-degrading enzymes such neprilysin insulin-degrading (IDE) brains. Taken together, our findings provide mechanistic foundation link demonstrating change favor β-amyloidogenesis via translational combination its substrate, APP.