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Relative increase in Alzheimer's disease of soluble forms of cerebral A beta amyloid protein precursor containing the Kunitz protease inhibitory domain
journal contribution
posted on 2023-05-17, 10:03 authored by Moir, RD, Lynch, T, Bush, AI, Whyte, S, Henry, A, Portbury, S, Multhaup, G, David SmallDavid Small, Tanzi, RE, Beyreuther, K, Masters, CLAlthough a number of studies have examined amyloid precursor protein (APP) mRNA levels in Alzheimer's disease (AD), no clear consensus has emerged as to whether the levels of transcripts for isoforms containing a Kunitz protease inhibitory (KPI)-encoded region are increased or decreased in AD. Here we compare AD and control brain for the relative amounts of APP protein containing KPI to APP protein lacking this domain. APP protein was purified from the soluble subcellular fraction and Triton X-100 membrane pellet extract of one hemisphere of AD (n = 10), normal (n = 7), and neurological control (n = 5) brains. The amount of KPI-containing APP in the purified protein samples was determined using two independent assay methods. The first assay exploited the inhibitory action of KPI-containing APP on trypsin. The second assay employed reflectance analysis of Western blots. The proportion of KPI-containing forms of APP in the soluble subcellular fraction of AD brains is significantly elevated (p < 0.01) compared with controls. Species containing a KPI domain comprise 32-41 and 76-77% of purified soluble APP from control and AD brains, respectively. For purified membrane-associated APP, 72-77 and 65-82% of control and AD samples, respectively, contain a KPI domain. Since KPI-containing species of APP may be more amyloidogenic (Ho, L., Fukuchi, K., and Yonkin, S. G. (1996) J. Biol. Chem. 271, 30929-30934), our findings support an imbalance of isoforms as one possible mechanism for amyloid deposition in sporadic AD.
History
Publication title
Journal of Biological ChemistryVolume
273Issue
9Pagination
5013-5019ISSN
0021-9258Department/School
Menzies Institute for Medical ResearchPublisher
Amer Soc Biochemistry Molecular Biology IncPlace of publication
9650 Rockville Pike, Bethesda, USA, Md, 20814-3996Rights statement
Copyright 1998 The American Society for Biochemistry and Molecular Biology, Inc.Repository Status
- Restricted