Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice.
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-beta peptide (A beta) 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 A beta1-40 on the neocortex reduced resting CBF in a dose-dependent fashion (-29% +/- 7% at 5 micromol/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%). A beta1-40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of A beta1-40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of A beta to generate reactive oxygen species, abolished A beta1-40 vasoactivity. The authors conclude that A beta1-40, but not A beta1-42, reproduces the cerebrovascular alterations observed in APP transgenics. Thus, A beta1-40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.
Niwa
K
K
Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, USA.
Carlson
G A
GA
Iadecola
C
C
D000109:Acetylcholine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001345:Autoradiography; D001920:Bradykinin / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006935:Hypercapnia / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016166:Free Radical Scavengers; D007476:Ionophores; D008665:Metalloporphyrins; D020030:Nitric Oxide Donors; D010446:Peptide Fragments; C110881:S-nitro-N-acetylpenicillamine; D014665:Vasodilator Agents; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013481:Superoxides; D000001:Calcimycin; D013482:Superoxide Dismutase; D010396:Penicillamine; D005947:Glucose; D000109:Acetylcholine; D001920:Bradykinin