, 2012).

It is, therefore, conceivable that in cases in which AD was diagnosed clinically there might have been a component of vascular pathology. New imaging and CSF biomarkers for the in vivo diagnosis of AD may provide additional insights into whether vascular factors are pathogenically linked to AD (Chui et al., 2012, Haight et al., 2013 and Purnell et al., 2009). Mounting evidence that Aβ has powerful vascular effects Selleckchem PLX-4720 also suggests a link between AD and vascular disease. Aβ1−40 constrict isolated cerebral and systemic blood vessels (Niwa et al., 2001, Paris et al., 2003 and Thomas et al., 1996), whereas application of Aβ1−40 to the exposed cerebral cortex of mice reduces CBF and impairs the increase in CBF induced by endothelium-dependent vasodilators and functional hyperemia (Niwa et al., 2000a and Niwa et al., 2000b). Similarly, functional hyperemia, endothelium-dependent responses and autoregulation are profoundly impaired in young mice overexpressing mutated forms of APP, in which brain Aβ is elevated, but there are no plaques, behavioral alterations, or reductions in resting glucose utilization (Niwa et al., 2000b, Niwa BMS-354825 mouse et al., 2002 and Tong et al., 2012). These data suggest that the cerebrovascular effects of Aβ are not attributable to CAA or amyloid plaques, and are not a consequence of neuronal energy

hypometabolism. APP-overexpressing mice have increased brain damage following occlusion of the middle cerebral artery (Koistinaho et al., 2002 and Zhang et al., 1997), an effect in part related to poor collateral circulation due to vascular dysregulation (Zhang et al., 1997). The vascular alterations induced by Aβ are abrogated by overexpression of the ROS scavenging enzyme superoxide dismutase or deficiency of the NADPH oxidase subunit NOX2 (Iadecola et al., 1999, Park et al., 2005 and Park also et al., 2008), implicating ROS produced by the

enzyme NADPH oxidase in the vascular dysfunction. The mechanisms of NADPH oxidase activation involve the Aβ-binding scavenger receptor CD36 (Park et al., 2011). Aged APP mice deficient in CD36 are protected from cerebrovascular alterations and behavioral deficits, effects associated with reduced CAA compared to controls, but no reduction of amyloid plaques (Park et al., 2013b). Thus, CD36, which is located in vascular and perivascular cells, may contribute to the accumulation of Aβ in cerebral blood vessels. Hypoperfusion and hypoxia caused by vascular insufficiency may also facilitate Aβ production by activating the APP cleavage enzyme β-secretase (Kitaguchi et al., 2009, Sun et al., 2006, Tesco et al., 2007 and Wen et al., 2004a). Cerebral ischemia promotes amyloid plaque formation (Garcia-Alloza et al., 2011, Kitaguchi et al., 2009 and Okamoto et al., 2012), and tau phosphorylation (Koike et al., 2010, Wen et al., 2007 and Wen et al., 2004b).