PMID- 37817156
OWN - NLM
STAT- MEDLINE
DCOM- 20231102
LR  - 20231120
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 20
IP  - 1
DP  - 2023 Oct 11
TI  - Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the 
      context of Alzheimer's disease and brain aging.
PG  - 233
LID - 10.1186/s12974-023-02914-7 [doi]
LID - 233
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-beta 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.
CI  - (c) 2023. BioMed Central Ltd., part of Springer Nature.
FAU - Corraliza-Gomez, Miriam
AU  - Corraliza-Gomez M
AD  - Instituto de Biomedicina y Genetica Molecular, Excellence Unit, University of 
      Valladolid-CSIC, Valladolid, Spain. miriam.corraliza@uva.es.
FAU - Bermejo, Teresa
AU  - Bermejo T
AD  - Instituto de Biomedicina y Genetica Molecular, Excellence Unit, University of 
      Valladolid-CSIC, Valladolid, Spain.
FAU - Lilue, Jingtao
AU  - Lilue J
AD  - Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
FAU - Rodriguez-Iglesias, Noelia
AU  - Rodriguez-Iglesias N
AD  - Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, 
      Spain.
AD  - Department of Neurosciences, University of the Basque Country, Leioa, Spain.
FAU - Valero, Jorge
AU  - Valero J
AD  - Institute of Neuroscience of Castilla y Leon-INCyL, University of Salamanca, 
      Salamanca, Spain.
AD  - Institute for Biomedical Research of Salamanca, Salamanca, Spain.
FAU - Cozar-Castellano, Irene
AU  - Cozar-Castellano I
AD  - Instituto de Biomedicina y Genetica Molecular, Excellence Unit, University of 
      Valladolid-CSIC, Valladolid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Madrid, Spain.
FAU - Arranz, Eduardo
AU  - Arranz E
AD  - Instituto de Biomedicina y Genetica Molecular, Excellence Unit, University of 
      Valladolid-CSIC, Valladolid, Spain.
FAU - Sanchez, Diego
AU  - Sanchez D
AD  - Instituto de Biomedicina y Genetica Molecular, Excellence Unit, University of 
      Valladolid-CSIC, Valladolid, Spain.
FAU - Ganfornina, Maria Dolores
AU  - Ganfornina MD
AD  - Instituto de Biomedicina y Genetica Molecular, Excellence Unit, University of 
      Valladolid-CSIC, Valladolid, Spain.
LA  - eng
GR  - "Margarita Salas postdoctoral grant for the training of young doctors"/Ministerio 
      de Universidades/
GR  - Predoctoral fellowship/Universidad de Valladolid/
GR  - PID2019-110496RB-C21/Ministerio de Ciencia e Innovacion/
GR  - PID2019-110911RB-I00/AEI/Ministerio de Ciencia e Innovacion/
GR  - VA086G18/Consejeria de Educacion, Junta de Castilla y Leon/
PT  - Journal Article
DEP - 20231011
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Amyloid beta-Peptides)
RN  - EC 3.4.24.56 (Insulysin)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Alzheimer Disease/metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - *Insulysin/genetics/metabolism/pharmacology
MH  - Microglia/metabolism
MH  - *Diabetes Mellitus, Type 2/genetics/metabolism
MH  - Brain/metabolism
MH  - Phenotype
PMC - PMC10566021
OTO - NOTNLM
OT  - Amyloid-beta endocytosis
OT  - Cytokine secretion
OT  - Inflammation
OT  - Insulin-degrading enzyme
OT  - Microglia
OT  - Microglial proliferation
OT  - Myelin phagocytosis
OT  - Oxidative stress
COIS- The authors declare that they have no competing interest.
EDAT- 2023/10/11 00:42
MHDA- 2023/11/02 12:44
PMCR- 2023/10/11
CRDT- 2023/10/10 23:55
PHST- 2023/06/14 00:00 [received]
PHST- 2023/09/28 00:00 [accepted]
PHST- 2023/11/02 12:44 [medline]
PHST- 2023/10/11 00:42 [pubmed]
PHST- 2023/10/10 23:55 [entrez]
PHST- 2023/10/11 00:00 [pmc-release]
AID - 10.1186/s12974-023-02914-7 [pii]
AID - 2914 [pii]
AID - 10.1186/s12974-023-02914-7 [doi]
PST - epublish
SO  - J Neuroinflammation. 2023 Oct 11;20(1):233. doi: 10.1186/s12974-023-02914-7.