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PMID:16997486

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Citation

Zhou, W, Scott, SA, Shelton, SB and Crutcher, KA (2006) Cathepsin D-mediated proteolysis of apolipoprotein E: possible role in Alzheimer's disease. Neuroscience 143:689-701

Abstract

Proteolysis of apolipoprotein E (apoE) may be involved in the pathogenesis of Alzheimer's disease (AD). We previously identified aspartic protease(s) as possibly contributing to the proteolysis of apoE in human brain homogenates. The current study used biochemical and immunohistochemical methods to examine whether cathepsin D (catD) and cathepsin E (catE), candidate aspartic proteases, may be involved in apoE proteolysis. CatD was found to proteolyze both lipid-free recombinant full-length human apoE and lipidated human plasma full-length apoE (apoE4/dipalmitoylphosphatidylcholine-reconstituted discs). CatE was found to proteolyze lipid-free recombinant human apoE to a much greater extent than lipidated apoE. This proteolysis, as well as proteolysis of human apoE added to brain homogenates from apoE-deficient mice, was inhibited by pepstatin A (an aspartic protease inhibitor), but not by phenylmethanesulfonyl fluoride (a serine protease inhibitor). The major apoE fragment obtained with catD included the receptor-binding domain and had an apparent molecular weight similar to that found in human brain homogenates. There was little immunoreactivity for catE in AD brain tissue sections. In contrast, qualitative and quantitative analyses of immunostained sections of the frontal cortex revealed that catD and apoE are colocalized in a subset of predominantly dense-core neuritic plaques and in some neurofibrillary tangles. A positive correlation was observed between estimated duration of illness and the percentage of apoE-positive plaques that were also catD-positive. These results suggest that aspartic proteases, catD in particular, may be involved in proteolysis of apoE and perhaps contribute to the generation of apoE fragments previously implicated in AD pathology.

Links

PubMed Online version:10.1016/j.neuroscience.2006.08.019

Keywords

Aged; Aged, 80 and over; Alzheimer Disease/metabolism; Alzheimer Disease/pathology; Animals; Apolipoproteins E/deficiency; Apolipoproteins E/metabolism; Blotting, Western/methods; Brain/drug effects; Brain/metabolism; Cathepsin D/metabolism; Cathepsin D/pharmacology; Cathepsin E/metabolism; Cathepsin E/pharmacology; Drug Interactions; Female; Humans; Immunohistochemistry/methods; Male; Mice; Mice, Knockout; Middle Aged; Neurofibrillary Tangles/drug effects; Neurofibrillary Tangles/metabolism; Pepstatins/pharmacology; Phenylmethylsulfonyl Fluoride/pharmacology; Phosphopyruvate Hydratase/metabolism; Plaque, Amyloid/drug effects; Plaque, Amyloid/metabolism; Postmortem Changes; Protease Inhibitors/pharmacology; Time Factors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CATD

involved_in

GO:0006508: proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P02649)

Seeded From UniProt

complete

HUMAN:CATD

enables

GO:0008233: peptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P02649)

Seeded From UniProt

complete

HUMAN:CATE

involved_in

GO:0006508: proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P02649)

Seeded From UniProt

complete

HUMAN:CATE

enables

GO:0008233: peptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P02649)

Seeded From UniProt

complete

MOUSE:CATD

enables

GO:0070001: aspartic-type peptidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • has_input:(UniProtKB:P02649)

Seeded From UniProt

complete

HUMAN:CATD

enables

GO:0008233: peptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_input:(UniProtKB:P02649)

Seeded From UniProt

complete

HUMAN:CATD

involved_in

GO:0006508: proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

has_input:(UniProtKB:P02649)

Seeded From UniProt

complete

HUMAN:CATD

involved_in

GO:0042159: lipoprotein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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