K. Niwa et al., Exogenous A beta 1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice, J CEREBR B, 20(12), 2000, pp. 1659-1668
Transgenic mice overexpressing the amyloid precursor protein (APP) have a p
rofound 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 responsi
ble for the cerebrovascular effects of APP overexpression. Cerebral blood f
low (CBF) was monitored by a laser-Doppler flowmeter in anesthetized-ventil
ated 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
mu mol/L) and attenuated the increase in CBF produced by the endothelium-d
ependent vasodilators acetylcholine (-41% +/- 8%), bradykinin (-39% +/- 9%)
, and the calcium ionophore A23187 (-37% +/- 5%). A beta1-40 did not influe
nce the CBF increases produced by the endothelium-independent vasodilators
S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 di
d not attenuate resting CBF or the CBF increases produced by endothelium-de
pendent vasodilators. Cerebrovascular effects of A beta1-40 were reversed b
y the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of met
hionine 35 with norleucine, a mutation that blocks the ability of A beta to
generate reactive oxygen species, abolished A beta1-40 vasoactivity. The a
uthors conclude that A beta1-40, but not A beta1-42, reproduces the cerebro
vascular alterations observed in APP transgenics. Thus, A beta1-40 could pl
ay a role in the cerebrovascular alterations observed in Alzheimer's dement
ia.