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Arch Neurol. 2002 Sep;59(9):1381-9.

Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease.

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  • 1Alzheimer Disease Research Unit, Center for Aging, Genetics, and Neurodegeneration, Massachusetts General Hospital-East, Bldg 114, Room 2010, 114 16th Street, Charlestown, MA 02129, USA.

Abstract

CONTEXT:

Amyloid plaques, a major pathological feature of Alzheimer disease (AD), are composed of an internal fragment of amyloid precursor protein (APP): the 4-kd amyloid-beta protein (Abeta). The metabolic processing of APP that results in Abeta formation requires 2 enzymatic cleavage events, a gamma-secretase cleavage dependent on presenilin, and a beta-secretase cleavage by the aspartyl protease beta-site APP-cleaving enzyme (BACE).

OBJECTIVE:

To test the hypothesis that BACE protein and activity are increased in regions of the brain that develop amyloid plaques in AD.

METHODS:

We developed an antibody capture system to measure BACE protein level and BACE-specific beta-secretase activity in frontal, temporal, and cerebellar brain homogenates from 61 brains with AD and 33 control brains.

RESULTS:

In the brains with AD, BACE activity and protein were significantly increased (P<.001). Enzymatic activity increased by 63% in the temporal neocortex (P =.007) and 13% in the frontal neocortex (P =.003) in brains with AD, but not in the cerebellar cortex. Activity in the temporal neocortex increased with the duration of AD (P =.008) but did not correlate with enzyme-linked immunosorbent assay measures of insoluble Abeta in brains with AD. Protein level was increased by 14% in the frontal cortex of brains with AD (P =.004), with a trend toward a 15% increase in BACE protein in the temporal cortex (P =.07) and no difference in the cerebellar cortex. Immunohistochemical analysis demonstrated that BACE immunoreactivity in the brain was predominantly neuronal and was found in tangle-bearing neurons in AD.

CONCLUSIONS:

The BACE protein and activity levels are increased in brain regions affected by amyloid deposition and remain increased despite significant neuronal and synaptic loss in AD.

Comment in

PMID:
12223024
[PubMed - indexed for MEDLINE]
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