Beta-secretase activity increases with aging in human, monkey, and mouse brain - PubMed (original) (raw)

Comparative Study

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

Hiroaki Fukumoto et al. Am J Pathol. 2004 Feb.

Abstract

Amyloid beta protein (A beta) 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 A beta 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 A beta 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 A beta 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 A beta, and potentially predisposes to Alzheimer's disease in humans.

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Figures

Figure 1

Figure 1

Formic acid-extractable Aβ measures in nontransgenic mouse (A), Tg2576 APP transgenic mouse (B), monkey (C), and human (D–F) brains with aging. In nontransgenic mice (A) and transgenic mice (B), Aβ levels were increased in 14- to 18-month-old mice (old) relative to 4-month-old mice (young) (*, analysis of variance; P < 0.001), reflecting significant increases in cortex (ctx) and cerebellum (cb), (†, posthoc _t_-test; P < 0.02). C: In rhesus monkey frontal (fr) and temporal (temp) cortices, there was a trend toward increased Aβ in the older monkeys (**, analysis of variance; P = 0.05). Aβ levels increased exponentially with age in human temporal cortex (D) and frontal cortex (E) (‡, P < 0.02) but not cerebellum (F).

Figure 2

Figure 2

BACE activity in nontransgenic mouse (A), Tg2576 APP transgenic mouse (B), monkey (C), and human (D–F) brains with aging. In nontransgenic mouse (A), transgenic mouse (B), and monkey (C) brains, BACE activity was increased in the old animals relative to the young animals (*, analysis of variance; P < 0.001), reflecting significant increases in each brain region (†, P < 0.05). BACE activity levels also increased with age in human temporal cortex (D), frontal cortex (E), and cerebellum (F) (‡, P < 0.03).

Figure 3

Figure 3

BACE protein levels in nontransgenic mouse (A), Tg2576 APP transgenic mouse (B), monkey (C), and human (D–F) brains with aging. There was no significant association of BACE protein levels with age in any of the cohorts.

Figure 4

Figure 4

Western blot of BACE (A) and pro-BACE (B) in human frontal cortices. There was no consistent change in the pattern of migration with aging.

Figure 5

Figure 5

The ratio of BACE activity to BACE protein (BACE act/prt) in nontransgenic mouse (A), Tg2576 APP transgenic mouse (B), monkey (C), and human (D–F) brains with aging. In nontransgenic mice (A) and transgenic mice (B), the BACE act/prt ratio was increased in the old mice relative to the young mice (*, analysis of variance; P < 0.001) reflecting significant increases in both cortex and cerebellum (†, posthoc; P < 0.01). In rhesus monkey (C), there was a trend toward increased BACE act/prt in the old monkeys relative to the young monkeys (**, analysis of variance; P = 0.07). In human brain, BACE act/prt increased with age in temporal cortex (D), frontal cortex (E), and cerebellum (F) (‡, P < 0.001).

Figure 6

Figure 6

BACE activity levels and Aβ levels in nontransgenic mouse (A), Tg2576 APP transgenic mouse (B), monkey (C), and human (D–F) brains. In nontransgenic mice (A) and transgenic mice (B), Aβ increased exponentially with increasing BACE activity levels in cortex and cerebellum (‡, P < 0.05). In monkey (C), there was no significant association between BACE activity levels and formic acid-extractable Aβ levels. In human brain, there were weak associations of BACE activity levels with Aβ40 levels in temporal cortex (D), and with Aβ40 and Aβ42 levels in frontal cortex (‡, P < 0.05) (E), but no association with Aβ levels in cerebellum (F).

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