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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

Citation

Moir, RD and Lynch, T and Bush, AI and Whyte, S and Henry, A and Portbury, S and Multhaup, G and Small, DH and Tanzi, RE and Beyreuther, K and Masters, CL, Relative increase in Alzheimer's disease of soluble forms of cerebral A beta amyloid protein precursor containing the Kunitz protease inhibitory domain, Journal of Biological Chemistry, 273, (9) pp. 5013-5019. ISSN 0021-9258 (1998) [Refereed Article]


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Copyright 1998 The American Society for Biochemistry and Molecular Biology, Inc.

DOI: doi:10.1074/jbc.273.9.5013

Abstract

Although 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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
Author:Small, DH (Professor David Small)
ID Code:75409
Year Published:1998
Web of Science® Times Cited:84
Deposited By:Research Division
Deposited On:2012-01-30
Last Modified:2012-06-26
Downloads:0

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