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. 2005 Feb 16;25(7):1769-77.
doi: 10.1523/JNEUROSCI.5207-04.2005.

NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide

Laibaik Park  1 , Josef Anrather, Ping Zhou, Kelly Frys, Rose Pitstick, Steven Younkin, George A Carlson, Costantino Iadecola
Affiliations

NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide

Laibaik Park et al. J Neurosci. .

Abstract

Overproduction of the amyloid beta (Abeta) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of Abeta on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the cerebrovascular dysregulation induced by Abeta. Thus, the free-radical production and the associated alterations in vasoregulation induced by Abeta are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91phox). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91phox. The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91phox-containing NADPH oxidase is the critical link between Abeta and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

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Figures

Figure 1.
Figure 1.
Effect of suffusion of Aβ1-40 (5 μm) on the mouse somatosensory cortex with or without the NADPH oxidase peptide assembly inhibitor gp91ds-tat (gp91-ds) or its scrambled version (sgp91-ds). Aβ attenuates resting CBF (a) and reduces CBF responses to whisker stimulation (b), acetylcholine (c), the calcium ionophore A23187 (d), bradykinin (e), and the NO donor SNAP (f). Aβ did not alter the vasodilation produced by the NO-independent vasodilator adenosine (g). The cerebrovascular effects of Aβ were abrogated by pretreatment with gp91ds-tat but not sgp91-ds. LDU, Laser-Doppler perfusion units.*p < 0.05; ANOVA and Tukey's test; n = 6 per group. Error bars represent SEM.
Figure 2.
Figure 2.
Effect of suffusion of Aβ1-40 (5 μm) on the somatosensory cortex of wild-type mice and mice lacking gp91phox, the catalytic subunit of NADPH oxidase. In gp91wt/wt, Aβ1-40 reduced resting CBF (a) and attenuated the increase in CBF elicited by whisker stimulation (b), acetylcholine (c), A23187 (d), and SNAP (e). Aβ1-40 was devoid of cerebrovascular effects in gp910/0. LDU, Laser-Doppler perfusion units. *p < 0.05; ANOVA and Tukey's test; n = 6 per group. Error bars represent SEM.
Figure 3.
Figure 3.
Cerebrovascular function in crosses between Tg2576 and gp910/0. Four groups of mice were studied: mice without the transgene and carrying wild-type gp91phox, mice carrying Tg2576 and wild-type for gp91phox, mice carrying the transgene and lacking gp91phox, and mice without the transgene and lacking gp91phox. Tg2576/gp91wt/wt mice exhibited attenuation of the increase in CBF produced by whisker stimulation (a), acetylcholine (b), A23187 (c), bradykinin (d), and the NO donor SNAP (e). The CBF response to adenosine was not altered (f). These cerebrovascular abnormalities were not observed in Tg2576/gp910/0 (a-e). gp910/0 mice had normal cerebrovascular reactivity (a-f). *p < 0.05; ANOVA and Tukey's test; n = 6 per group. Error bars represent SEM.
Figure 4.
Figure 4.
Brain levels of Aβ1-40 and Aβ1-42 in Tg2576 with (Tg2576/gp91wt/wt) and without (Tg2576/gp910/0) gp91phox. Both SDS-soluble (a) and SDS-insoluble (b) Aβ were examined. n = 6 per group. Error bars represent SEM.
Figure 5.
Figure 5.
ROS production in somatosensory cortex assessed by hydroethidine microfluorography. Aβ1-40 neocortical superfusion (5 μm) increases ROS production in wild-type mice (a, b) but not in mice lacking gp91phox (a, c). The increase in ROS production produced by Aβ is blocked by the NADPH oxidase assembly inhibitor gp91ds-tat (gp91ds) (d) but not by its scrambled version (sgp91-ds) (e). ROS overproduction is present in Tg2576 with wild-type gp91phox (g) but not in Tg2576 lacking gp91phox (f). The bar graphs in h represent group data corresponding to a-g. Scale bar, 50 μm. RLU, Relative fluorescent light units. *p < 0.05; ANOVA and Tukey's test; n = 6 per group. Error bars represent SEM.
Figure 6.
Figure 6.
Effect of NOS inhibition on the cerebrovascular actions of Aβ peptides. The neuronal NOS inhibitor 7-NI attenuated resting CBF (a) and the CBF response to whisker stimulation (b) but not acetylcholine or adenosine (c, d). Application of Aβ1-40 after 7-NI did not further reduce resting CBF (a) or the responses to whisker stimulation (b). The absence of Aβ1-40 effects could not beat tributed to the fact that the response was already maximally attenuated, because the Na+ channel blocker TTX further attenuated the CBF response to whisker stimulation (b). LDU, Laser-Doppler perfusion units. *p < 0.05 from Ringer's solution; #p < 0.05 from 7-NI; ANOVA and Tukey's test; n = 6 per group. Error bars represent SEM.
Figure 7.
Figure 7.
Effect of NOS inhibition on the cerebrovascular actions of APP overexpression. In wild-type mice, the nonselective NOS inhibitor l-NNA attenuated resting CBF (a) and the CBF response to whisker stimulation (b) or acetylcholine (c). The CBF increase produced by adenosine was not affected (d). The neuronal NOS inhibitor 7-NI attenuated resting CBF and the CBF response to whisker stimulation but not acetylcholine or adenosine (a-d). In Tg2576, 7-NI or l-NNA did not attenuate resting CBF (a) and the increase in CBF produced by whisker stimulation (b) or acetylcholine (c). Responses to adenosine were not affected (d). The absence of effects on functional hyperemia could not be attributed to the fact that the response was already maximally reduced, because TTX further attenuated the CBF response to whisker stimulation (b). 7-NI enhanced the response to ACh in Tg2576 (c), but the significance of this finding is unclear. LDU, Laser-Doppler perfusion units. *p < 0.05 from Ringer's solution in wild-type mice; #p < 0.05 from 7-NI in wild-type and Tg2576 mice; &p < 0.05 from Ringer's solution in Tg2576 mice; ANOVA and Tukey's test; n = 6 per group. Error bars represent SEM.
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