Exogenous Aβ1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice
Exogenous Aβ1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice
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DOI：
10.1097/00004647-200012000-00005
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发表时间：
2000-12-01
影响因子：
6.3
通讯作者：
Iadecola, C
中科院分区：
文献类型：
--
作者：
Niwa, K;Carlson, GA;Iadecola, C
过表达淀粉样前体蛋白（APP）的转基因小鼠在内皮依赖性脑血管反应中有严重的损伤，这种损伤被超氧化物清除剂超氧化物歧化酶（SOD）抵消。作者研究了淀粉样β肽（A β）是否与APP过度表达的脑血管效应有关。用激光多普勒流量计监测麻醉通气小鼠脑血流（CBF）。A β 1 -40对新皮质的灌注以剂量依赖性方式减少静息CBF（5 μ mol/L时为-29% +/- 7%），并减弱了由内皮依赖性血管扩张剂乙酰胆碱（-41% +/- 8%）、缓激肽（-39% +/- 9%）和钙离子载体A23187（-37% +/- 5%）产生的CBF增加。A β 1 -40不影响由内皮非依赖性血管扩张剂S-亚硝基-N-乙酰青霉胺和高碳酸血症产生的CBF增加。相比之下，A β 1 -42没有减弱静息CBF或内皮依赖性血管扩张剂产生的CBF增加。超氧化物清除剂SOD或MnTBAP可逆转A β 1 -40的脑血管效应。此外，用正亮氨酸取代甲硫氨酸35（一种阻断A β产生活性氧的能力的突变），消除了A β 1 -40的血管活性。作者得出结论，A β 1 -40，而不是A β 1 -42，再现了在APP转基因中观察到的脑血管改变。因此，A β 1 -40可能在阿尔茨海默氏痴呆症中观察到的脑血管改变中发挥作用。
Transgenic mice overexpressing the amyloid precursor protein (APP) have a profound impairment in endothelium-dependent cerebrovascular responses that is counteracted by the superoxide scavenger superoxide dismutase (SOD). The authors investigated whether the amyloid-beta peptide (A beta) is responsible for the cerebrovascular effects of APP overexpression. Cerebral blood flow (CBF) was monitored by a laser-Doppler flowmeter in anesthetized-ventilated mice equipped with a cranial window. Superfusion of A beta1-40 on the neocortex reduced resting CBF in a dose-dependent fashion (-29% +/- 7% at 5 mu mol/L) and attenuated the increase in CBF produced by the endothelium-dependent vasodilators acetylcholine (-41% +/- 8%), bradykinin (-39% +/- 9%), and the calcium ionophore A23187 (-37% +/- 5%). A beta1-40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of A beta1-40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of A beta to generate reactive oxygen species, abolished A beta1-40 vasoactivity. The authors conclude that A beta1-40, but not A beta1-42, reproduces the cerebrovascular alterations observed in APP transgenics. Thus, A beta1-40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.