Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease.
BACKGROUND
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.
Fukumoto
Hiroaki
H
Alzheimer Disease Research Unit, Center for Aging, Genetics, and Neurodegeneration, Massachusetts General Hospital-East, Bldg 114, Room 2010, 114 16th Street, Charlestown, MA 02129, USA.
Cheung
Bonnie S
BS
Hyman
Bradley T
BT
Irizarry
Michael C
MC
D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology*; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D002525:Cerebellar Cortex / Q000378:metabolism; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019579:Neocortex / Q000201:enzymology*; D058225:Plaque, Amyloid / Q000201:enzymology; D011233:Precipitin Tests; D016708:Synaptophysin / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016708:Synaptophysin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human