SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein

Abstract

Peptides derived from proteolytic processing of the beta-amyloid precursor protein (APP), including the amyloid-beta peptide, are important for the pathogenesis of Alzheimer's dementia. We found that transgenic mice overexpressing APP have a profound and selective impairment in endothelium-dependent regulation of the neocortical microcirculation. Such endothelial dysfunction was not found in transgenic mice expressing both APP and superoxide dismutase-1 (SOD1) or in APP transgenics in which SOD was topically applied to the cerebral cortex. These cerebrovascular effects of peptides derived from APP processing may contribute to the alterations in cerebral blood flow and to neuronal dysfunction in Alzheimer's dementia.

Neurovascular function in Alzheimer's disease patients and experimental models

“…Interestingly, and in accord with the in vitro and in vivo superfusion data (see Exogenous Ab application), endothelial dysfunction does not occur in young APP mice co-overexpressing the O 2 KÀ scavenger, superoxide dismutase (SOD), or receiving neocortical SOD application (Iadecola et al, 1999). Similarly, there is no impairment in the evoked CBF response to whisker stimulation or endothelium-dependent (ACh, bradykinin, and calcium ionophore A23187) and -independent (SNAP) vasoactive stimuli in young APP mice lacking the gp91 phox NADPH oxidase catalytic subunit (Park et al, 2005).…”

“…However, before any visible CAA, the animal literature suggests that soluble Ab potently deregulates cerebrovascular function by activating a free radical cascade that substantially reduces vasodilator half-life and imparts oxidative damage to cerebrovascular enzymes and receptors (Price et al, 1997;Iadecola et al, 1999;Tong et al, 2005;Park et al, 2005Park et al, , 2008. Soluble Ab also potentiates constrictions to endothelin-1 (ET-1) when applied to isolated human cerebral arteries collected after rapid autopsies, seemingly via a proinflammatory cascade (Townsend et al, 2002;Paris et al, 2003).…”

“…Young APP mice (2 to 3 months old) devoid of plaque pathology and neuronal loss display an attenuated perfusion response to endothelium-dependent vasodilators, and exaggerated CBF decrease to a constrictor, the thromboxane A 2 analog U46619 (Iadecola et al, 1999). In addition, APP mice feature impaired autoregulatory ability, a homeostatic mechanism that ensures constant blood flow during changes in mean arterial pressure.…”

“…Animals thus lack protection against ischemia (Niwa et al, 2002b;Takeda et al, 2009). The CBF increase to hypercapnia and endothelium-independent vasodilators such as SNAP (S-nitroso-N-acetylpenicillamine) or SNP (sodium nitroprusside) is either maintained (Iadecola et al, 1999;Niwa et al, 2000a;Christie et al, 2001;Shin et al, 2007) or impaired (Park et al, 2005;Han et al, 2008) in young Tg2576 mice, suggesting variable degree of smooth muscle dysfunction. However, the response to whisker stimulation is diminished, with the reduction being commensurate to levels of soluble brain Ab 1À40 and Ab 1À42 encountered in the various APP lines tested (Tg6209, Tg2123, and Tg2576) (Niwa et al, 2000a) (Table 1).…”

Dietary nitrate supplementation improves sprint and high-intensity intermittent running performance

“…Similar to the serial 3s subtraction task, the Stroop task assesses the capacity for information processing (Besner and Roberts 2005) and performance in these tasks is related to the functioning of the prefrontal cortex. NO is pivotal to a number of cerebral processes including neurotransmission, vasodilation and neurovascular coupling (Aamand et al 2013;Iadecola et al 1999;Piknova et al 2011;Rifkind et al 2007). Dietary NO 3 -has been shown to improve regional brain perfusion (Presley et al 2011), attenuate cerebral O 2 extraction during mental processing (Thompson et al 2014), and enhance coupling of cerebral blood flow to neuronal activity (Aamand et al 2013).…”