Exogenous Aβ1–40 Reproduces Cerebrovascular Alterations Resulting from Amyloid Precursor Protein Overexpression in Mice

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Abstract
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-β peptide (Aβ) 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 Aβ1–40 on the neocortex reduced resting CBF in a dose-dependent fashion (−29% ± 7% at 5 μmol/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%). Aβ1–40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, Aβ1–42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of Aβ1–40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of Aβ to generate reactive oxygen species, abolished Aβ1–40 vasoactivity. The authors conclude that Aβ1–40, but not Aβ1–42, reproduces the cerebrovascular alterations observed in APP transgenics, Thus, Aβ1–40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.