Aβ-peptides enhance vasoconstriction in cerebral circulation

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Abstract
Amyloid-β (Aβ)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of Aβ on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with Aβ1–40 (0.1–10 μM), but not with the reverse peptide Aβ40–1, reduced resting CBF (−29 ± 4% at 5 μM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 ± 3% at 5 μM; P < 0.05). Aβ1–40 or Aβ1–42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of Aβ to produce free radicals, abolished its vascular effects. Nanomolar concentrations of Aβ1–40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (−16 ± 3% at 100 nM;P < 0.05). We conclude that Aβ acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that Aβ-induced production of reactive oxygen species plays a role in this effect. The vascular actions of Aβ may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.