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 -Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease
Hiroaki Fukumoto, PhD;
Bonnie S. Cheung, BS;
Bradley T. Hyman, MD, PhD;
Michael C. Irizarry, MD
Arch Neurol. 2002;59:1381-1389.
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- protein (A). The metabolic processing of APP that
results in A formation requires 2 enzymatic cleavage events, a  -secretase
cleavage dependent on presenilin, and a -secretase cleavage by the aspartyl
protease -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 -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 A 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.
From the Alzheimer Disease Research Unit, Department of Neurology,
Massachusetts General Hospital, Charlestown.
RELATED ARTICLE
Explaining the Cause of the Amyloid Burden in Alzheimer Disease
Roger N. Rosenberg
Arch Neurol. 2002;59(9):1367-1368.
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