Oxidative stress affects processing of amyloid precursor protein in vascular endothelial cells

Abstract

BackgroundOxidative stress is thought to be a key player in the pathogenesis of neurodegenerative dementia, including Alzheimer’s disease (AD). It has been assumed that oxidative stress contributes to the ß-amyloid deposition in cerebral blood vessels.MethodsIn order to prove this hypothesis, we examined the effect of oxidative stress on the processing of amyloid precursor protein (APP) in primary endothelial cells (EC) derived from cerebral cortical tissue of transgenic Tg2576 mice. Following exposure of EC by 1 μM hydrogen peroxide for up to 48 hours, formation and secretion of APP cleavage products sAPPα and sAPPß into the culture medium as well as the expression of endothelial APP were assessed.ResultsOxidative stress resulted in enhanced secretion of sAPPß into the culture medium as compared to controls (absence of hydrogen peroxide), which was accompanied by an increased APP expression, induction of VEGF synthesis, nitric oxide and oxygen free radicals productions, and differential changes of endothelial phospo-p42/44 MAPK expression.ConclusionThe data suggest that oxidative stress may represent a major risk factor in causing Aß deposition in the brain vascular system by initiating the amyloidogenic route of endothelial APP processing. The enhanced β-secretase activity following oxidative stress exposure, possibly promoted by phosphorylation of p42/44 MAPK.

Proteomic analysis of sperm proteins in infertile men with high levels of reactive oxygen species

“…Amyloid precursor protein (APP) is known to be ubiquitously expressed in mammalian cells, with a broad tissue distribution and a hallmark of Alzheimer's disease (Silva et al., ). APP protein has been widely studied and reported to be associated with oxidative stress (Muche, Arendt, & Schliebs, ). Some studies have shown that amyloid precursor‐like protein 2 (APLP2) is highly expressed in testis and spermatozoa but failed to prove the presence of APP in mammalian spermatozoa (Silva et al., ).…”

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium

“…Moreover, the effects of the various cell types targeted (via SR-BI) may be additive, multiplicative, or otherwise synergistic. This therapeutic approach receives added impetus from continual findings of cerebrovascular pathology (Beishon et al 2017;Goldwaser et al 2016;Hishikawa et al 2016;Kapasi and Schneider 2016;Kelleher and Soiza 2013;Malojcic et al 2017;McAleese et al 2016;Muche et al 2017;Nelson et al 2016;Nielsen et al 2017;Noh et al 2016;Perrotta et al 2016;Raz et al 2016;Weekman et al 2016) and brain arterial aging (Calabrese et al 2016;Cooper and Mitchell 2016;Gutierrez et al 2016;Kelleher and Soiza 2013;Malojcic et al 2017;Nagata et al 2016;Raz et al 2016;Toth et al 2017) accompanying Alzheimer's disease. Similarly, there is an apparent endothelium-dysfunction involvement Bhat 2015;Carradori et al 2016;Chao et al 2016;Devraj et al 2016;Di Marco et al 2015;Festoff et al 2016;Gangoda et al 2016;Hishikawa et al 2016;Hostenbach et al 2016;Kahlil et al 2016;Kelleher and Soiza 2013;Koizumi at al.…”

“…Similarly, there is an apparent endothelium-dysfunction involvement Bhat 2015;Carradori et al 2016;Chao et al 2016;Devraj et al 2016;Di Marco et al 2015;Festoff et al 2016;Gangoda et al 2016;Hishikawa et al 2016;Hostenbach et al 2016;Kahlil et al 2016;Kelleher and Soiza 2013;Koizumi at al. 2016;Koster et al 2016;Muche et al 2017;Qosa et al 2016;Roberts et al 2016;Salmina et al 2010;Shang et al 2016; in Alzheimer's disease as well as in its major risk factors (Austin et al 2015;Austin and Katusic 2016;Bogush et al 2017;Chao et al 2016;Devraj et al 2016;Festoff et al 2016;Gangoda et al 2016;Iadecola 2016;Kahlil et al 2016;Kalaria et al 2016;Kamat et al 2016;Katusic and Austin 2016;Kelleher and Soiza 2013;Khan et al 2016;Kyrtsos and Baras 2015;Perrotta et al 2016;Roberts et al 2016;Shang et al 2016;Sheen and Sheu 2016;Toda and Okamura 2016;Toth et al 2017;Uiterwijk et al 2016;Vanhoutte et al 2017;…”

“…He, and his coworkers, further suggested that widespread microvascular pathology may result from loss of the perivascular neural plexus (denervating microangiopathy), which could result in a failing blood-brain barrier and subsequent development of the disease (Scheibel 1987;Scheibel et al 1989). Over these past decades, a frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed (Malojcic et al 2017;Muche et al 2017;Raz et al 2016); as a result, there has been difficulty in clinically differentiating between Alzheimer's disease, vascular dementia, and mixed Alzheimer's disease/vascular dementia (Calabrese et al 2016;McAleese et al 2016;Raz et al 2016;Tarantini et al 2016). In fact, vascular dementia is considered the second most common cause of cognitive impairment after Alzheimer's disease in the elderly (Calabrese et al 2016).…”

Nanotherapy for Early Dementia: Targeting Senile Dementia

“…This therapeutic approach receives added impetus from continual findings of cerebrovascular pathology (Beishon et al 2017;Goldwaser et al 2016;Hishikawa et al 2016;Kapasi and Schneider 2016;Kelleher and Soiza 2013;Malojcic et al 2017;McAleese et al 2016;Muche et al 2017;Nelson et al 2016;Nielsen et al 2017;Noh et al 2016;Perrotta et al 2016;Raz et al 2016;Weekman et al 2016) and brain arterial aging (Calabrese et al 2016;Cooper and Mitchell 2016;Gutierrez et al 2016;Kelleher and Soiza 2013;Malojcic et al 2017;Nagata et al 2016;Raz et al 2016;Toth et al 2017) accompanying Alzheimer's disease. Similarly, there is an apparent endothelium-dysfunction involvement Bhat 2015;Carradori et al 2016;Chao et al 2016;Devraj et al 2016;Di Marco et al 2015;Festoff et al 2016;Gangoda et al 2016;Hishikawa et al 2016;Hostenbach et al 2016;Kahlil et al 2016;Kelleher and Soiza 2013;Koizumi at al.…”