Abstract TP486: Role of Beta-Site Amyloid Precursor Protein-Cleaving Enzyme 2 in the Metabolism of Amyloid Precursor Protein in Human Brain Microvascular Endothelial Cells

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Tongrong He ◽  
Zvonimir S Katusic
Keyword(s):  
Protein Expression ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Protective Function ◽  
Protein Levels ◽  
Genetic Inactivation ◽  
Amyloidogenic Processing ◽  
Protein Expressions ◽  
App Metabolism

Under physiological conditions, β-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) cleaves APP within Aβ sequence thereby functioning like a α-secretase. However, BACE2 could also function as a conditional β-secretase during aging, contributing to Alzheimer’s disease pathogenesis. To date the physiological functions of BACE2 in endothelium are largely unknown. The present study is therefore designed to investigate the role of BACE2 in APP metabolism in human BMECs. Cultured human BMECs (passage 5-6 or passage 22) were treated with BACE2siRNA (30 nM, for 3 days), levels of soluble APPα (sAPPα, a neurotrophic product of non-amyloidogenic processing of APP) and Aβ40 in the supernatant were measured. In human BMECs (passage 5-6), genetic inactivation of BACE2 significantly decreased production of sAPPα (n=12, P<0.05), but had no effect on production of Aβ40 (n=9, P>0.05). BACE2siRNA treatment significantly suppressed APP protein expression (n=7, P<0.05), but augmented protein levels of BACE1 (n=7, P<0.05). Genetic inactivation of BACE2 did not change protein levels of mature ADAM10 (n=7, P>0.05). Thus, reduced sAPPα secretion by BACE2siRNA treatment is likely caused not only by decreased α-secretase-like function of BACE2, but also by reduced APP expression. We further examined the effects of BACE2siRNA in senescent human BMECs. In cultured human BMECs (passage 22), protein expressions of senescent markers (p 21Cip1 and p 16INK4a ) were significantly increased (n=4, P<0.05). Genetic inactivation of BACE2 in senescent human BMECs also significantly suppressed secretion of sAPPα (n=8, P<0.05), but did not affect Aβ40 production (n=8, P>0.05). BACE2-siRNA treatment significantly inhibited protein expressions of APP and mature ADAM10 (n=7, P<0.05), but did not change BACE1 protein expression (n=7, P>0.05). Thus in senescent human BMECs, reduced APP expression and impaired α-processing may play important roles in the decreased sAPPα production. Since our previous studies have demonstrated that endothelial production of sAPPα significantly contributes to the sAPPα content in the hippocampus, our current findings suggests that inhibition of BACE2 could impair protective function of sAPPα in the hippocampus.

scholarly journals Impairment of amyloid precursor protein alpha-processing in cerebral microvessels of type 1 diabetic mice

2017 ◽  
Vol 39 (6) ◽  
pp. 1085-1098
Author(s):  
Tongrong He ◽  
Ruohan Sun ◽  
Anantha VR Santhanam ◽  
Livius V d'Uscio ◽  
Tong Lu ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Local Concentration ◽  
Microvascular Endothelium ◽  
Cerebral Microvessels ◽  
Protein Levels ◽  
Enhanced Production ◽  
Amyloidogenic Processing

The mechanisms underlying dysfunction of cerebral microvasculature induced by type 1 diabetes (T1D) are not fully understood. We hypothesized that in cerebral microvascular endothelium, α-processing of amyloid precursor protein (APP) is impaired by T1D. In cerebral microvessels derived from streptozotocin (STZ)-induced T1D mice protein levels of APP and its α-processing enzyme, a disintegrin and metalloprotease 10 (ADAM10) were significantly decreased, along with down-regulation of adenylate cyclase 3 (AC3) and enhanced production of thromboxane A2 (TXA2). In vitro studies in human brain microvascular endothelial cells (BMECs) revealed that knockdown of AC3 significantly suppressed ADAM10 protein levels, and that activation of TXA2 receptor decreased APP expression. Furthermore, levels of soluble APPα (sAPPα, a product of α-processing of APP) were significantly reduced in hippocampus of T1D mice. In contrast, amyloidogenic processing of APP was not affected by T1D in both cerebral microvessels and hippocampus. Most notably, studies in endothelial specific APP knockout mice established that genetic inactivation of APP in endothelium was sufficient to significantly reduce sAPPα levels in the hippocampus. In aggregate, our findings suggest that T1D impairs non-amyloidogenic processing of APP in cerebral microvessels. This may exert detrimental effect on local concentration of neuroprotective molecule, sAPPα, in the hippocampus.

scholarly journals Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Fawaz Alasmari ◽  
Musaad A. Alshammari ◽  
Abdullah F. Alasmari ◽  
Wael A. Alanazi ◽  
Khalid Alhazzani
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurofibrillary Tangles ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Cytokine Release ◽  
Efflux Transport ◽  
Protein Levels ◽  
Amyloid A ◽  
The Brain

Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer’s disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.

Amyloidogenic Processing of Amyloid Precursor Protein: Evidence of a Pivotal Role of Glutaminyl Cyclase in Generation of Pyroglutamate-Modified Amyloid-β†

Biochemistry ◽  
2008 ◽  
Vol 47 (28) ◽  
pp. 7405-7413 ◽  
Author(s):  
Holger Cynis ◽  
Eike Scheel ◽  
Takaomi C. Saido ◽  
Stephan Schilling ◽  
Hans-Ulrich Demuth
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Pivotal Role ◽  
Glutaminyl Cyclase ◽  
Amyloidogenic Processing

Effects of altered RTN3 expression on BACE1 activity and Alzheimer’s neuritic plaques

2017 ◽  
Vol 28 (2) ◽  
pp. 145-154 ◽  
Author(s):  
Md Golam Sharoar ◽  
Riqiang Yan
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Neuritic Plaques ◽  
Amyloid Peptides ◽  
Protein Levels ◽  
Bace1 Expression ◽  
Β Amyloid ◽  
Tubular Endoplasmic Reticulum ◽  
Bace1 Activity

AbstractReticulon 3 (RTN3), which is a member of the reticulon family of proteins, has a biochemical function of shaping tubular endoplasmic reticulum. RTN3 has also been found to interact with β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which initiates the generation of β-amyloid peptides (Aβ) from amyloid precursor protein. Aβ is the major proteinaceous component in neuritic plaques, which constitute one of the major pathological features in brains of Alzheimer’s disease (AD) patients. Mice deficient in or overexpressing RTN3 have altered amyloid deposition through effects on BACE1 expression and activity. In this review, we will summarize the current findings concerning the role of RTN3 in AD pathogenesis and demonstrate that RTN3 protein levels act as age-dependent modulators of BACE1 activity and Aβ deposition during the pathogenic progression of AD.

scholarly journals Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

2016 ◽  
Vol 37 (1) ◽  
pp. 106-122 ◽  
Author(s):  
Tongrong He ◽  
Anantha Vijay R Santhanam ◽  
Tong Lu ◽  
Livius V d'Uscio ◽  
Zvonimir S Katusic
Keyword(s):  
Endothelial Cells ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Cerebral Microvessels ◽  
Protein Levels ◽  
Selective Agonist ◽  
Ip Receptor

We tested hypothesis that activation of the prostacyclin (PGI2) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI2, iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPα (sAPPα). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor δ (PPARδ) in human brain microvascular endothelial cells. PPARδ-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARδ) upregulated ADAM10 and increased production of sAPPα. Genetic deletion of endothelial PPARδ (ePPARδ−/−) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPα. In vivo treatment with GW501516 increased sAPPα content in hippocampus of wild type mice but not in hippocampus of ePPARδ−/− mice. Our findings identified previously unrecognized role of IP-PPARδ signal transduction pathway in the production of sAPPα in cerebral microvasculature.

Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1164-1173
Author(s):  
Siju Ellickal Narayanan ◽  
Nikhila Sekhar ◽  
Rajalakshmi Ganesan Rajamma ◽  
Akash Marathakam ◽  
Abdullah Al Mamun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Late Onset ◽  
Precursor Protein ◽  
Brain Disorder ◽  
Amyloid Aβ ◽  
T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

Follicular-fluid soluble amyloid precursor protein levels are increased among women with polycystic ovarian syndrome undergoing IVF

2014 ◽  
Vol 102 (3) ◽  
pp. e261-e262
Author(s):  
S.-L. Chen ◽  
P. Li ◽  
F.-H. Duan ◽  
X. Chen ◽  
J. Niu
Keyword(s):  
Amyloid Precursor Protein ◽  
Follicular Fluid ◽  
Polycystic Ovarian Syndrome ◽  
Precursor Protein ◽  
Protein Levels ◽  
Ovarian Syndrome

scholarly journals The Role of Presenilin-1 in the γ-Secretase Cleavage of the Amyloid Precursor Protein of Alzheimer's Disease

2000 ◽  
Vol 275 (3) ◽  
pp. 1525-1528 ◽  
Author(s):  
Jean-Noël Octave ◽  
Rachid Essalmani ◽  
Bernadette Tasiaux ◽  
Jean Menager ◽  
Christian Czech ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1

scholarly journals Decreased Expression of GPER1 Gene and Protein in Goiter

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Raquel Weber ◽  
Ana Paula Santin Bertoni ◽  
Laura Walter Bessestil ◽  
Ilma Simoni Brum ◽  
Tania Weber Furlanetto
Keyword(s):  
Estrogen Receptor ◽  
Quantitative Polymerase Chain Reaction ◽  
Thyroid Tissue ◽  
Chain Reaction ◽  
Normal Thyroid ◽  
Protein Levels ◽  
Protein Expressions ◽  
Polymerase Chain ◽  
G Protein Coupled

Goiter is more common in women, suggesting that estrogen could be involved in its physiopathology. The presence of classical estrogen receptors (ERαand ERβ) has been described in thyroid tissue, suggesting a direct effect of estrogen on the gland. A nonclassic estrogen receptor, the G-protein-coupled estrogen receptor (GPER1), has been described recently in several tissues. However, in goiter, the presence of this receptor has not been studied yet. We investigated GPER1 gene and protein expressions in normal thyroid and goiter using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. In normal thyroid (n=16) and goiter (n=19), GPER1 gene was expressed in all samples, while GPER1 protein was expressed in all samples of normal thyroid (n=15) but in only 72% of goiter samples (n=13). When comparing GPER1 gene and protein levels in both conditions, gene expression and protein levels were higher in normal thyroid than in goiter, suggesting a role of this receptor in this condition. Further studies are needed to elucidate the role of GPER1 in normal thyroid and goiter.

β-Amyloid precursor protein and tau protein levels are differently regulated in human cerebellum compared to brain regions vulnerable to Alzheimer's type neurodegeneration

2010 ◽  
Vol 485 (3) ◽  
pp. 162-166 ◽  
Author(s):  
Mirsada Čaušević ◽  
Umbreen Farooq ◽  
Simon Lovestone ◽  
Richard Killick
Keyword(s):  
Amyloid Precursor Protein ◽  
Tau Protein ◽  
Brain Regions ◽  
Precursor Protein ◽  
Protein Levels ◽  
Human Cerebellum ◽  
Β Amyloid
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