RT info:eu-repo/semantics/article
T1 Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
A1 Corraliza Gómez, Miriam
A1 Bermejo Pastor, Teresa
A1 Lilue, Jingtao
A1 Rodriguez Iglesias, Noelia
A1 Valero Gómez Lobo, Jorge
A1 Cózar Castellano, Irene
A1 Arranz Sanz, Eduardo
A1 Sánchez Romero, Diego
A1 Ganfornina Álvarez, María Dolores
K1 Bioquímica
K1 Gerontología
K1 Neurobiología
K1 Enfermedades del sistema nervioso
K1 Enzima degradadora de insulina
K1 Microglía
K1 Fagocitosis de mielina
K1 Endocitosis de beta-amiloide
K1 Inflamación
K1 Estrés oxidativo
K1 Proliferación microglial
K1 Secreción de citocinas
K1 2403 Bioquímica
K1 2490 Neurociencias
K1 3207.11 Neuropatología
AB The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. 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-β 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.
PB Springer Nature
SN 1742-2094
YR 2023
FD 2023
LK https://uvadoc.uva.es/handle/10324/82941
UL https://uvadoc.uva.es/handle/10324/82941
LA eng
NO Journal of Neuroinflammation, 2023, vol. 20, p. 1-21.
NO Producción Científica
DS UVaDOC
RD 21-feb-2026