scholarly journals P1-031: Ascidians as a novel invertebrate model system to study APP processing and amyloid-beta plaque formation

2008 ◽  
Vol 4 ◽  
pp. T214-T214
Author(s):  
Michael J. Virata ◽  
Robert W. Zeller
Keyword(s):  
Amyloid Beta ◽  
Model System ◽  
Plaque Formation ◽  
App Processing ◽  
Invertebrate Model

scholarly journals Cholesterol Lowering Drugs Reduce APP Processing to Aβ by Inducing APP Dimerization

2020 ◽  
pp. mbc.E20-05-0345
Author(s):  
Vanessa F. Langness ◽  
Rik van der Kant ◽  
Utpal Das ◽  
Louie Wang ◽  
Rodrigo dos Santos Chaves ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Cholesterol Metabolism ◽  
Amyloid Plaques ◽  
Bimolecular Fluorescence Complementation ◽  
App Processing ◽  
Transfected Cells ◽  
Human Neurons ◽  
Induced Changes ◽  
Aβ Production ◽  
Cholesterol Binding

Amyloid beta (Aβ) is a major component of amyloid plaques which are a key pathological hallmark found in brains of Alzheimer's Disease (AD) patients. We show that statins are effective at reducing Aβ in human neurons from non-demented control (NDC) subjects, as well as subjects with familial AD (FAD), and sporadic AD (SAD). Aβ is derived from Amyloid Precursor Protein (APP) through sequential proteolytic cleavage by BACE1 and γ-secretase. While previous studies have shown that cholesterol metabolism regulates APP processing to Aβ, the mechanism is not well understood. We used iPSC derived neurons and bimolecular fluorescence complementation assays in transfected cells to elucidate how altering cholesterol metabolism influences APP processing. Altering cholesterol metabolism using statins decreased generation of sAPPβ and increased levels of full-length APP (flAPP), indicative of reduced processing of APP by BACE1. We further show that statins decrease flAPP interaction with BACE1 and enhance APP dimerization. Additionally, statin induced changes in APP dimerization and APP-BACE1 are dependent on cholesterol binding to APP. Our data indicate that statins reduce Aβ production by decreasing BACE1 interaction with flAPP and suggest that this process may be regulated through competition between APP dimerization and APP cholesterol binding.

scholarly journals Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer's mice

2007 ◽  
Vol 178 (5) ◽  
pp. 829-841 ◽  
Author(s):  
Ping He ◽  
Zhenyu Zhong ◽  
Kristina Lindholm ◽  
Lilian Berning ◽  
Wendy Lee ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Transgenic Mice ◽  
Learning And Memory ◽  
Tumor Necrosis ◽  
Death Receptor ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Plaque Formation ◽  
App Processing ◽  
Necrosis Factor

The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid β protein (Aβ)–induced neuronal death. However, the function of TNFR1 in Aβ plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1−/−) inhibits Aβ generation and diminishes Aβ plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced β-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-κB pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Aβ plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.

scholarly journals Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling

2019 ◽  
Author(s):  
Claire S. Durrant ◽  
Karsten Ruscher ◽  
Olivia Sheppard ◽  
Michael P. Coleman ◽  
Ilknur Özen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Precursor Protein ◽  
Vascular Pathology ◽  
Amyloid Precursor Protein Processing ◽  
App Processing ◽  
Bace1 Inhibition

AbstractAmyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, over-production of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD.SignificanceIn this study, we show that targeting amyloid beta processing provides an opportunity to selectively target tip cell filopodia-driven angiogenesis and develop therapeutic targets for vascular dysfunction related to aberrant angiogenesis in AD. Our data provide the first evidence for a safe level of BACE1 inhibition that can normalize excess angiogenesis in AD, without inducing vascular deficits in healthy tissue. Our findings may pave the way for the development of new angiogenesis dependent therapeutic strategies in Alzheimer’s Disease.

scholarly journals Association of aBACE1Gene Polymorphism with Parkinson’s Disease in a Norwegian Population

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Johannes Lange ◽  
Kristin Aaser Lunde ◽  
Camilla Sletten ◽  
Simon Geir Møller ◽  
Ole-Bjørn Tysnes ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Beta ◽  
Population Based ◽  
App Processing ◽  
Norwegian Population ◽  
Increased Risk ◽  
Beta Peptide ◽  
Genetic Level ◽  
And Control

Background. Parkinson’s disease (PD) and Alzheimer’s disease (AD) share pathological features, including amyloid-beta pathology. Amyloid-beta peptide is generated by sequential proteolysis of amyloid precursor protein (APP), and genetic variations in the processing pathway genes have been found to increase the risk of AD; however, the contribution in PD is unknown.Methods. The aim of this study was to investigate whether candidate polymorphisms in five genes (ADAM10,BACE1,BACE2,PSEN2, andCLU) involved in the APP processing pathway affect PD risk in a population-based cohort of patients with incident PD and control subjects from the Norwegian ParkWest study.Results. We found an association of rs638405 inBACE1with increased risk of PD, thus providing a novel link, at the genetic level, between amyloid-beta pathology and PD.

Sign in / Sign up

Export Citation Format

Share Document