β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease

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 (PϽ.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.