RGD Reference Report - Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. - Rat Genome Database

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Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme.

Authors: Vekrellis, K  Ye, Z  Qiu, WQ  Walsh, D  Hartley, D  Chesneau, V  Rosner, MR  Selkoe, DJ 
Citation: Vekrellis K, etal., J Neurosci. 2000 Mar 1;20(5):1657-65.
RGD ID: 1627576
Pubmed: PMID:10684867   (View Abstract at PubMed)
PMCID: PMC6772918   (View Article at PubMed Central)

Progressive cerebral accumulation of amyloid beta-protein (Abeta) is an early and invariant feature of Alzheimer's disease. Little is known about how Abeta, after being secreted, is degraded and cleared from the extracellular space of the brain. Defective Abeta degradation could be a risk factor for the development of Alzheimer's disease in some subjects. We reported previously that microglial cells release substantial amounts of an Abeta-degrading protease that, after purification, is indistinguishable from insulin-degrading enzyme (IDE). Here we searched for and characterized a role for IDE in Abeta degradation by neurons, the principal cell type that produces Abeta. Whole cultures of differentiated pheochromocytoma (PC12) cells and primary rat cortical neurons actively degraded endogenously secreted Abeta via IDE. However, unlike that in microglia, IDE in differentiated neurons was not released but localized to the cell surface, as demonstrated by biotinylation. Undifferentiated PC12 cells released IDE into their medium, whereas after differentiation, IDE was cell associated but still degraded Abeta in the medium. Overexpression of IDE in mammalian cells markedly reduced the steady-state levels of extracellular Abeta(40) and Abeta(42), and the catalytic site mutation (E111Q) abolished this effect. We observed a novel membrane-associated form of IDE that is approximately 5 kDa larger than the known cytosolic form in a variety of cells, including differentiated PC12 cells. Our results support a principal role for membrane-associated and secreted IDE isoforms in the degradation and clearance of naturally secreted Abeta by neurons and microglia.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
amyloid-beta clearance involved_inIMP 1627576PMID:10684867ARUK-UCL 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cell surface located_inIDA 1627576PMID:10684867ARUK-UCL 
cell surface  IDA 1627576differentiated PC12 pheochromocytoma cells and primary cortical neuronsRGD 
extracellular space located_inIDA 1627576PMID:10684867ARUK-UCL 
extracellular space  IDA 1627576undifferentiated PC12 pheochromocytoma cellsRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ide  (insulin degrading enzyme)


Additional Information