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

2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Claire S. Durrant ◽  
Karsten Ruscher ◽  
Olivia Sheppard ◽  
Michael P. Coleman ◽  
Ilknur Özen
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Vascular Pathology ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Beta Peptides ◽  
App Processing ◽  
Sprouting Angiogenesis ◽  
Organotypic Brain Slice ◽  
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, overproduction 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.

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 Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase

2003 ◽  
Vol 163 (1) ◽  
pp. 97-107 ◽  
Author(s):  
Zoe Scholefield ◽  
Edwin A. Yates ◽  
Gareth Wayne ◽  
Augustin Amour ◽  
William McDowell ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulfate ◽  
Structural Characteristics ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide ◽  
App Processing ◽  
Sites Of Action

Cleavage of amyloid precursor protein (APP) by the Alzheimer's β-secretase (BACE1) is a key step in generating amyloid β-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with β-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by α-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing.

Cell line construction and maintenance for Lyso-IP and Endo-IP analysis of amyloid precursor protein processing v1

2021 ◽  
Author(s):  
Hankum Park ◽  
Frances V Hundley ◽  
Harper JW
Keyword(s):  
Amyloid Precursor Protein ◽  
Cell Line ◽  
Quantitative Proteomics ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
App Processing ◽  
293 Cells ◽  
Line Construction ◽  
App Gene

Lyso-IP is a method that allows for the isolation of lysosomes for proteomics and metabolomics (dx.doi.org/10.17504/protocols.io.bybjpskn; dx.doi.org/10.17504/protocols.io.bx9hpr36). We have developed an analogous approach for purification of early/sorting endosomes (Endo-IP). In addition, we have found that endolysosomal purification via Lyso-IP and Endo-IP can be coupled with a quantitative proteomics workflow to obtain snapshots of Amyloid Precursor Protein (APP) processing to its Aβ products (Park et al. in submission). Here, we describe methods for cell line construction and maintenance of 293 cells with TMEM192-3xHA and 3xFLAG-EEA1, which are used for lysosome and endosome purification, respectively, with the addition of patient mutations to APP promotes processing. Cells with endogenously tagged TMEM192 and stably expressing FLAG-EEA1 are referred to as 293EL cells, for Endo-IP and Lyso-IP. These cells were also prepared in a form that has a deletion of the APP gene (293EL;APP-/-) and the same cells reconstituted with a lentivirus stably expressing APPSw;T700N to allow functional analysis of APP processing.

scholarly journals Filling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processing

2017 ◽  
Vol 313 (5) ◽  
pp. R585-R593 ◽  
Author(s):  
Rebecca E. K. MacPherson
Keyword(s):  
Insulin Resistance ◽  
Amyloid Precursor Protein ◽  
Significant Risk ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Amyloid Precursor Protein Processing ◽  
Direct Effects ◽  
App Processing ◽  
Β Amyloid ◽  
Exercise Induced

Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer’s disease (AD). Several studies have demonstrated that diet-induced obesity, inactivity, and insulin resistance exacerbate the neuropathological hallmarks of AD. The aggregation of β-amyloid peptides is one of these hallmarks. β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to β-amyloid peptide formation. Understanding how BACE1 content and activity are regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has been proven to reduce the risk of AD as well as decrease β-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and discusses our current understanding of the direct of effect of exercise on β-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as β-amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD-related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia.

scholarly journals Phosphorylation of FE65 Ser610 by serum- and glucocorticoid-induced kinase 1 modulates Alzheimer's disease amyloid precursor protein processing

2015 ◽  
Vol 470 (3) ◽  
pp. 303-317 ◽  
Author(s):  
Wan Ning Vanessa Chow ◽  
Jacky Chi Ki Ngo ◽  
Wen Li ◽  
Yu Wai Chen ◽  
Ka Ming Vincent Tam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
App Processing

Phosphorylation of FE65 Ser610 by serum- and glucocorticoid-induced kinase 1 (SGK1) attenuates amyloid precursor protein (APP) processing via regulation of FE65–APP interaction.

Low density lipoprotein increases amyloid precursor protein processing to amyloidogenic pathway in differentiated SH-SY5Y cells

Biologia ◽  
2017 ◽  
Vol 72 (2) ◽  
Author(s):  
Panit Yamchuen ◽  
Rattima Jeenapongsa ◽  
Sutisa Nudmamud-Thanoi ◽  
Nanteetip Limpeanchob
Keyword(s):  
Amyloid Precursor Protein ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Neuroblastoma Cells ◽  
Density Lipoprotein ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Low Density ◽  
App Processing

AbstractHypercholesterolemia has been considered as a risk factor for Alzheimer’s disease (AD). In addition to low density lipoprotein (LDL), oxidized LDL plays some roles in AD pathology. Neurodegenerative effect of oxidized LDL was supported by the increased oxidative stress in neurons. To further investigate the role of oxidized LDL, the present study aimed to test its effect on amyloid precursor protein (APP) processing. The release of soluble APP (sAPP) was evaluated in differentiated SH-SY5Y neuroblastoma cells exposed to native (non-oxidized) or oxidized human LDL including mildly and fully oxidized LDL (mox- and fox-LDL). Non-amyloidogenic and amyloidogenic pathways were investigated using specific antibody against sAPP

scholarly journals FE65: Roles beyond amyloid precursor protein processing

2015 ◽  
Vol 20 (1) ◽  
Author(s):  
Wan Ning Vanessa Chow ◽  
Hei Nga Maggie Cheung ◽  
Wen Li ◽  
Kwok-Fai Lau
Keyword(s):  
Amyloid Precursor Protein ◽  
Synapse Formation ◽  
Adaptor Protein ◽  
Ubiquitin Proteasome System ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Developmentally Regulated ◽  
App Processing ◽  
Neuronal Processes ◽  
Initial Work

AbstractFE65 is a brain-enriched, developmentally regulated adaptor protein that was first identified as a binding partner of amyloid precursor protein (APP), an important molecule in Alzheimer’s disease. FE65 possesses three protein interaction domains, including an N-terminal WW domain and two C-terminal phosphotyrosine-binding (PTB) domains. It is capable of mediating the assembly of multimolecular complexes. Although initial work reveals its roles in APP processing and gene transactivation, increasing evidence suggests that FE65 participates in more diverse biological processes than originally anticipated. This article discusses the role of FE65 in signal transduction during cell stress and protein turnover through the ubiquitin-proteasome system and in various neuronal processes, including neurogenesis, neuronal migration and positioning, neurite outgrowth, synapse formation and synaptic plasticity, learning, and memory.

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