β-secretase activity increases with aging in human, monkey, and mouse brain

Amyloid beta protein (Abeta) accumulates in the brains of aging humans, amyloid precursor protein (APP) transgenic mouse lines, and rhesus monkeys. We tested the hypothesis that aging was associated with increased activity of the beta-site amyloid precursor protein cleaving enzyme (beta-secretase, BACE) in brain. We evaluated BACE activity, BACE protein, and formic acid-extractable Abeta levels in cohorts of young (4 months old) and old (14 to 18 months old) nontransgenic mice (n = 16) and Tg2576 APP transgenic mice (n = 17), young (4.4 to 12.7 years old) and old (20.9 to 30.4 years old) rhesus monkeys (n = 17), and a wide age range (18 to 92 years old) of nondemented human brains (n = 25). Aging was associated with increased brain Abeta levels in each cohort. Furthermore BACE activity increased significantly with age in mouse, monkey, and human brains, independent of brain region. BACE protein levels, however, were unchanged with age. BACE activity correlated with formic acid-extractable Abeta levels in transgenic mouse , nontransgenic mouse, and human cortex, but not in monkey brain. These data suggest that an age-related increase of BACE activity contributes to the increased production and accumulation of brain Abeta, and potentially predisposes to Alzheimer's disease in humans.