Brain and circulating levels of Aβ1-40 differentially contribute to vasomotor dysfunction in the mouse brain.

BACKGROUND AND PURPOSE Amyloid-β (Aβ), a peptide that accumulates in the brain and circulates in the blood of patients with Alzheimer disease, alters the regulation of cerebral blood flow and may contribute to the brain dysfunction underlying the dementia. However, the contributions of brain and circulating Aβ1-40 to the vascular dysfunction have not been elucidated. METHODS We used transgenic mice overexpressing mutated forms of the amyloid precursor protein in which Aβ1-40 is elevated in blood and brain (Tg-2576) or only in brain (Tg-SwDI). Mice were equipped with a cranial window, and the increase in cerebral blood flow induced by neural activity (whisker stimulation), or by topical application of endothelium-dependent vasodilators, was assessed by laser-Doppler flowmetry. RESULTS The cerebrovascular dysfunction was observed also in Tg-SwDI mice, but despite ≈40% higher levels of brain Aβ1-40, the effect was less marked than in Tg-2576 mice. Intravascular administration of Aβ1-40 elevated plasma Aβ1-40 and enhanced the dysfunction in Tg-SwDI mice, but not in Tg-2576 mice. CONCLUSIONS The results provide evidence that Aβ1-40 acts on distinct luminal and abluminal vascular targets, the deleterious cerebrovascular effects of which are additive. Furthermore, the findings highlight the importance of circulating Aβ1-40 in the cerebrovascular dysfunction and may provide insight into the cerebrovascular alterations in conditions in which elevations in plasma Aβ1-40 occur.