title: The predominant form of the amyloid beta-protein precursor in human brain is protease nexin 2.
abstract: The amyloid beta protein and the amyloid beta-protein precursor (APP) are major constituents of senile plaques and cerebrovascular deposits in patients with Alzheimer disease and Down syndrome. Most human tissues contain mRNA that encodes forms of APP that contain the Kunitz protease inhibitor (KPI+) domain. A major 120-kDa protein corresponding to this KPI+ mRNA is also found in these tissues. This protein is identical to the protease inhibitor protease nexin 2. Brain contains an additional mRNA species that encodes a form of APP that lacks the KPI domain (KPI-). This latter mRNA has been suggested to encode a 105-kDa KPI- form of APP protein also found in brain. Using protease inhibitory functional assays, we show that both the 105-kDa and 120-kDa APP proteins in normal and Alzheimer disease brain contain the KPI domain. Moreover, KPI domain-specific precipitation assays reveal that KPI- forms of APP protein represent less than 14% of total brain APP. Lastly, an enriched fraction from total brain homogenate contains proteolytic activity that can process the purified 120-kDa KPI+ form of APP into a 105-kDa form, resulting in a high-molecular-mass doublet identical to that seen in brain. These findings indicate that although KPI- APP mRNA is abundant in brain, little corresponding protein is present. Thus, KPI+ APP protein (equivalent to protease nexin 2) is the predominant form of APP in human brain.
authors.affiliation: Department of Microbiology, University of California, Irvine 92717.
authors.forename: W E
authors.initials: WE
authors.lastname: Van Nostrand
authors.forename: J S
authors.initials: JS
authors.lastname: Farrow
authors.forename: S L
authors.initials: SL
authors.lastname: Wagner
authors.forename: R
authors.initials: R
authors.lastname: Bhasin
authors.forename: D
authors.initials: D
authors.lastname: Goldgaber
authors.forename: C W
authors.initials: CW
authors.lastname: Cotman
authors.forename: D D
authors.initials: DD
authors.lastname: Cunningham
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000502:physiology* / Q000503:physiopathology; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D002846:Chromatography, Affinity; D004815:Epidermal Growth Factor / Q000032:analysis / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000378:metabolism; D058255:Protease Nexins; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics*; D011956:Receptors, Cell Surface; D012016:Reference Values
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D011480:Protease Inhibitors; D058255:Protease Nexins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D004815:Epidermal Growth Factor