Alterations in Cerebral Blood Flow and Glucose Utilization in Mice Overexpressing the Amyloid Precursor Protein

Niwa, Kiyoshi; Kazama, Ken; Younkin, Steven G.; Carlson, George A.; Iadecola, Costantino

doi:10.1006/nbdi.2001.0460

Cited by 193 publications

(151 citation statements)

References 31 publications

Supporting

Mentioning

139

Contrasting

Order By: Relevance

“…For example, Iadecola and coworkers have shown that young APP transgenic mice (Tg2576) exposed to elevated levels of Aβ 40 and Aβ 42 (but no CAA) have reduced baseline cerebral blood flow (CBF) and decreased CBF responses to topical vasodilators (23,24,26). We have shown similar CV deficits in young Tg2576 mice (13).…”

supporting

confidence: 56%

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Han

Zhou

Johnson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

109

100

View full text Add to dashboard Cite

Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.Alzheimer's disease | cerebral amyloid angiopathy | reactive oxygen species | NADPH oxidase | vasomotor dysfunction

show abstract

supporting

confidence: 56%

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Han

Zhou

Johnson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

109

100

View full text Add to dashboard Cite

show abstract

“…Reduction in resting CBF of a magnitude similar to that reported in Tg2576 (Niwa et al, 2002a) and in AD (Jagust, 2000) are not sufficient to produce ischemic cell dysfunction or death (Hossmann, 1994). However, such reductions in CBF can attenuate protein synthesis (Mies et al, 1991), a process that is essential for learning and memory (Martin et al, 2000;Milekic and Alberini, 2002).…”

Section: Discussionmentioning

confidence: 92%

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

Park¹,

Anrather²,

Zhou³

et al. 2005

J. Neurosci.

219

228

View full text Add to dashboard Cite

Overproduction of the amyloid ␤ (A␤) 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 A␤ 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 A␤. Thus, the free-radical production and the associated alterations in vasoregulation induced by A␤ are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91 phox ). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91 phox . The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91 phox -containing NADPH oxidase is the critical link between A␤ and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

show abstract

“…Amyloid precursor protein mice: Transgenic mice overexpressing mutated human APP with or without presenilin overproduce Ab and develop cerebrovascular dysfunction as an early feature, often before several other neuropathological and behavioral AD symptoms (Iadecola et al, 1999;Niwa et al, 2000aNiwa et al, , 2002aPark et al, 2005;Tong et al, 2005;Takeda et al, 2009). 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).…”

Section: Transgenic Mouse Modelsmentioning

confidence: 99%

“…Furthermore, it was unclear in the latter study if neuronal dysfunction had a role. Quantitative radioautographical determination of CGU showed intact resting and evoked glucose usage in Tg2123 mice (Niwa et al, 2000a), but a subsequent study showed reduced basal glucose utilization in Tg2576 mice that are derived from a different background strain and produce higher Ab levels (Niwa et al, 2002a). Recently, Takeda et al (2009) adjusted the magnitude of whisker stimulation so as to equalize somatosensory evoked potentials recorded at the site of CBF measurement.…”

Section: Transgenic Mouse Modelsmentioning

confidence: 99%

Neurovascular function in Alzheimer's disease patients and experimental models

Nicolakakis

Hamel

2011

J Cereb Blood Flow Metab

131

118

View full text Add to dashboard Cite

The ability of the brain to locally augment glucose delivery and blood flow during neuronal activation, termed neurometabolic and neurovascular coupling, respectively, is compromised in Alzheimer's disease (AD). Since perfusion deficits may hasten clinical deterioration and have been correlated with negative treatment outcome, strategies to improve the cerebral circulation should form an integral element of AD therapeutic efforts. These efforts have yielded several experimental models, some of which constitute AD models proper, others which specifically recapture the AD cerebrovascular pathology, characterized by anatomical alterations in brain vessel structure, as well as molecular changes within vascular smooth muscle cells and endothelial cells forming the bloodbrain barrier. The following paper will present the elements of AD neurovascular dysfunction and review the in vitro and in vivo model systems that have served to deepen our understanding of it. It will also critically evaluate selected groups of compounds, the FDA-approved cholinesterase inhibitors and thiazolidinediones, for their ability to correct neurovascular dysfunction in AD patients and models. These and several others are emerging as compounds with pleiotropic actions that may positively impact dysfunctional cerebrovascular, glial, and neuronal networks in AD.

show abstract

Alterations in Cerebral Blood Flow and Glucose Utilization in Mice Overexpressing the Amyloid Precursor Protein

Cited by 193 publications

References 31 publications

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

Neurovascular function in Alzheimer's disease patients and experimental models

Contact Info

Product

Resources

About