Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid β-Protein

摘要: The causes of cerebral accumulation amyloid β-protein (Aβ) in most cases Alzheimer's disease (AD) remain unknown. We recently found that homozygous deletion the insulin-degrading enzyme (IDE) gene mice results an early and marked elevation Aβ. Both genetic linkage allelic association IDE region chromosome 10 have been reported families with late-onset AD. For to a valid candidate for AD on functional grounds, it must be shown partial loss function can still alter Aβ degradation, but without causing early, severe brain Here, we show naturally occurring missense mutations well-characterized rat model type 2 diabetes mellitus (DM2) result decreased catalytic efficiency significant ∼15 30% deficit degradation both insulin Endogenously secreted 40 42 are significantly elevated primary neuronal cultures from animals mutations, there is no increase steady-state levels rodent up age 14 months. conclude occurring, loss-of-function sufficient cause DM2 also impair regulation levels, apparently compensate during life span rat. Our findings relevance emerging evidence suggesting may AD-risk gene, epidemiological relationships among hyperinsulinemia, DM2,