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Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-\u03b2 management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.<\/jats:p>","DOI":"10.1186\/s12974-023-02914-7","type":"journal-article","created":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T03:28:36Z","timestamp":1696994916000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer\u2019s disease and brain aging"],"prefix":"10.1186","volume":"20","author":[{"given":"Miriam","family":"Corraliza-Gomez","sequence":"first","affiliation":[]},{"given":"Teresa","family":"Bermejo","sequence":"additional","affiliation":[]},{"given":"Jingtao","family":"Lilue","sequence":"additional","affiliation":[]},{"given":"Noelia","family":"Rodriguez-Iglesias","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Valero","sequence":"additional","affiliation":[]},{"given":"Irene","family":"Cozar-Castellano","sequence":"additional","affiliation":[]},{"given":"Eduardo","family":"Arranz","sequence":"additional","affiliation":[]},{"given":"Diego","family":"Sanchez","sequence":"additional","affiliation":[]},{"given":"Maria Dolores","family":"Ganfornina","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,10,11]]},"reference":[{"key":"2914_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","volume":"7","author":"DS Knopman","year":"2021","unstructured":"Knopman DS, Amieva H, Petersen RC, Ch\u00e9telat G, Holtzman DM, Hyman BT, et al. 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