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¹ Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada H3A 2B4

Abstract

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 β peptide (Aβ) 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 Aβ 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 Aβ 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 Aβ-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-β1 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.

(Received 4 July 2007; accepted after revision 19 September 2007; first published online 2 October 2007)
Corresponding author E. Hamel: Montreal Neurological Institute, 3801 University Street, Montréal, QC, Canada, H3A 2B4. Email: edith.hamel{at}mcgill.ca

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