Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease

被引:89
作者
Hamel, E. [1 ]
Nicolakakis, N. [1 ]
Aboulkassim, T. [1 ]
Ongali, B. [1 ]
Tong, X-K. [1 ]
机构
[1] McGill Univ, Montreal Neurol Inst, Lab Cerebrovasc Res, Montreal, PQ H3A 2B4, Canada
关键词
D O I
10.1113/expphysiol.2007.038729
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Several factors have been implicated in Alzheimer's disease (AD) but there is no definite conclusion as to the main pathogenic agents. Mutations in the amyloid precursor protein (APP) that lead to increased production of amyloid beta peptide (A beta) are associated with the early-onset, familial forms of AD. However, in addition to ageing, the most common risk factors for the sporadic, prevalent form of AD are hypertension, hypercholesterolaemia, ischaemic stroke, the ApoE4 allele and diabetes, all characterized by a vascular pathology. In AD, the vascular pathology includes accumulation of A beta in the vessel wall, vascular fibrosis, and other ultrastructural changes in constituent endothelial and smooth muscle cells. Moreover, the ensuing chronic cerebral hypoperfusion has been proposed as a determinant factor in the accompanying cognitive deficits. In transgenic mice that overexpress mutated forms of the human APP (APP mice), the increased production of A beta results in vascular oxidative stress and loss of vasodilatory function. The culprit molecule, superoxide, triggers the synthesis of other reactive oxygen species and the sequestration of nitric oxide (NO), thus impairing resting cerebrovascular tone and NO-dependent dilatations. The A beta-induced cerebrovascular dysfunction can be completely abrogated in aged APP mice with antioxidant therapy. In contrast, in mice that overproduce an active form of the cytokine transforming growth factor-beta 1 and recapitulate the vascular structural changes seen in AD, antioxidants have no beneficial effect on the accompanying cerebrovascular deficits. This review discusses the beneficial role and limitations of antioxidant therapy in AD cerebrovascular pathology.
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页码:116 / 120
页数:5
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