Mechanisms of peripheral microvascular dysfunction in transgenic mice overexpressing the Alzheimer's disease amyloid Aβ protein

Freshly prepared soluble amyloid (A beta) peptide has been reported to have vascular actions both in vitro and in vivo. This study was designed to examine the in vivo microvascular effects of A beta in two skin microvascular model systems that might reflect possible short and long-term vascular effects of this peptide. Short-term vascular effects were examined using freshly prepared soluble A beta(1-40) peptide superfused over naive rat skin microvasculature for 15 min. Peripheral microvascular functional changes in 9-months-old transgenic (Tg) mice overexpressing soluble A beta in the brain, peripheral circulation and other tissues, were also examined. Microvascular responses were monitored using laser Doppler flowmetry from the base of a blister raised on the hind footpad of the animals. Endothelial-dependent and independent vasodilatation responses (VD) were examined using acetylcholine (ACh) and sodium nitroprusside (SNP) respectively. The exposure of naive rat skin microvasculature to A beta(1-40) resulted in an immediate vasoconstriction (VC) that prevented ACh but not SNP from inducing a subsequent VD response. The vascular effects of A beta(1-40) were reversed by antioxidants (superoxide dismutase and catalase) and an endothelin A (ETA) receptor antagonist (BQ-123). Tg mice overexpressing soluble A beta and C100 showed significant reductions in both endothelial-dependent and endothelial-independent VD that were also reversed by antioxidants and BQ-123. In conclusion, this study provided evidence to support the notion of peripheral vascular effects of A beta in vivo and present novel evidence for alterations in endothelial and smooth muscle cell function in peripheral skin microvasculature in Tg mice overexpressing A beta and C100. We suggest that skin microvasculature is a useful model to examine the mechanisms underlying the vascular actions of the A beta protein.