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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.

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