IDE, short for Insulin-degrading enzyme, is an evolutionarily conserved zinc-dependent metallopeptidase. It plays a crucial role in various biological processes. Besides degrading insulin, IDE can cleave many substrates in vitro, including amyloid beta peptides, suggesting its potential link in the pathophysiology between Alzheimer's disease (AD) and type 2 diabetes (T2D) [1].

In IDE knockout (IDE-KO) mice, a specific induction of microgliosis was found in the hippocampus, and the performance on hippocampal-dependent memory tests in 12-month-old mice was influenced by IDE gene dose [1]. Additionally, IDE absence in primary microglial cultures altered microglial responses to environmental signals, resulting in impaired modulation of phenotypic states [1]. In Klf9-/-mice, which exhibit impaired cognitive function, overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content, indicating that IDE-mediated Aβ degradation is important in AD-related cognitive function [2].

In conclusion, IDE is a significant enzyme involved in multiple biological functions, especially in relation to AD and T2D. The use of IDE-KO mouse models has revealed its role in microglial phenotypes, hippocampal-dependent memory, and Aβ degradation in the context of AD, providing valuable insights into the underlying disease mechanisms.