Amyloid β protein (Aβ) 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 β-site amyloid precursor protein cleaving enzyme (β-secretase, BACE) in brain. We evaluated BACE activity, BACE protein, and formic acid-extractable Aβ 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 Aβ 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 Aβ 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 Aβ, and potentially predisposes to Alzheimer's disease in humans.
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Supported by the National Institutes of Health (AG15453 to B.T.H. and AG05134 to Massachusetts Alzheimer Disease Research Center; AG00001 to Boston University, RR00165 to Emory University, PHS MH/NS 31862 to Harvard Brain Tissue Resource Center); the University of Maryland Developmental Brain and Tissue Bank for Developmental Disorders; the American Federation for Aging Research Beeson Award (to M.C.I.); the Harvard University W.F. Milton Fund (to M.C.I.); the J.D. French Foundation, Los Angeles, CA (to M.C.I.); and Takeda Chemical Industries, Osaka, Japan (to H.F.).
