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.

Control of β-Site Amyloid Precursor Protein-Cleaving Enzyme-1 Expression by Protein Kinase C-λ/ι and Nuclear Factor κ-B

2021 ◽  
Vol 19 ◽  
Author(s):  
Mini P. Sajan ◽  
Michael Leitges ◽  
Colin Park ◽  
David M. Diamond ◽  
Jin Wu ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Proinflammatory Cytokine ◽  
Insulin Treatment ◽  
Precursor Protein ◽  
Nuclear Factor ◽  
Diabetic Mice ◽  
Aβ Peptides ◽  
Protein Levels ◽  
Total Body ◽  
The Brain

Βackground: β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of Aβ-peptides that form Aβ-plaque in Alzheimer’s disease. Methods: Reportedly, acute insulin treatment in normal mice, and hyperinsulinemia in high-fat-fed (HFF) obese/diabetic mice, increase BACE1 activity and levels of Aβ-peptides and phospho- -thr-231-tau in the brain; moreover, these effects are blocked by PKC-λ/ι inhibitors. However, as chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to further examine PKC-λ/ι requirements. We found that total-body heterozygous PKC-λ knockout reduced acute stimulatory effects of insulin and chronic effects of hyperinsulinemia in HFF/obese/diabetic mice, on brain PKC-λ activity and production of Aβ1-40/42 and phospho-thr-231-tau. This protection in HFF mice may reflect that hepatic PKC-λ haploinsufficiency prevents the development of glucose intolerance and hyperinsulinemia. Results: On the other hand, heterozygous knockout of PKC-λ markedly reduced brain levels of BACE1 protein and mRNA, and this may reflect diminished activation of nuclear factor kappa-B (NFκB), which is activated by PKC-λ and increases BACE1 and proinflammatory cytokine transcription. Accordingly, whereas intravenous administration of aPKC inhibitor diminished aPKC activity and BACE1 levels by 50% in the brain and 90% in the liver, nasally-administered inhibitor reduced aPKC activity and BACE1 mRNA and protein levels by 50-70% in the brain while sparing the liver. Additionally, 24-hour insulin treatment in cultured human-derived neurons increased NFκB activity and BACE1 levels, and these effects were blocked by various PKC-λ/ι inhibitors. Conclusion: PKC-λ/ι controls NFκB activity and BACE1 expression; PKC-λ/ι inhibitors may be used nasally to target brain PKC-λ/ι or systemically to block both liver and brain PKC-λ/ι, to regulate NFκB-dependent BACE1 and proinflammatory cytokine expression.

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.

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.

scholarly journals Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines

Neuroscience ◽  
2010 ◽  
Vol 169 (1) ◽  
pp. 344-356 ◽  
Author(s):  
K.J. Lee ◽  
C.E.H. Moussa ◽  
Y. Lee ◽  
Y. Sung ◽  
B.W. Howell ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Dendritic Spines ◽  
Beta Amyloid ◽  
Precursor Protein

scholarly journals Polarized sorting of beta-amyloid precursor protein and its proteolytic products in MDCK cells is regulated by two independent signals.

1995 ◽  
Vol 128 (4) ◽  
pp. 537-547 ◽  
Author(s):  
C Haass ◽  
E H Koo ◽  
A Capell ◽  
D B Teplow ◽  
D J Selkoe
Keyword(s):  
Amino Acids ◽  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Mdck Cells ◽  
Membrane Vesicles ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Amyloid A ◽  
Membrane Spanning ◽  
Chloride Treatment

Progressive cerebral deposition of the amyloid (A beta) beta-protein is an early and invariant feature of Alzheimer's disease. A beta is derived by proteolysis from the membrane-spanning beta-amyloid precursor protein (beta APP). beta APP is processed into various secreted products, including soluble beta APP (APPs), the 4-kD A beta peptide, and a related 3-kD peptide (p3). We analyzed the mechanisms regulating the polarized basolateral sorting of beta APP and its proteolytic derivatives in MDCK cells. Deletion of the last 32 amino acids (residues 664-695) of the beta APP cytoplasmic tail had no influence on either the constitutive approximately 90% level of basolateral sorting of surface beta APP, or the strong basolateral secretion of APPs, A beta, and p3. However, deleting the last 42 amino acids (residues 654-695) or changing tyrosine 653 to alanine altered the distribution of cell surface beta APP so that approximately 40-50% of the molecules were inserted apically. In parallel, A beta was now secreted from both surfaces. Surprisingly, this change in surface beta APP had no influence on the basolateral secretion of APPs and p3. This result suggests that most beta APP molecules which give rise to APPs in MDCK cells are cleaved intracellularly before reaching the surface. Consistent with this conclusion, we readily detected intracellular APPs in carbonate extracts of isolated membrane vesicles. Moreover, ammonium chloride treatment resulted in the equal secretion of APPs into both compartments, as occurs with other non-membranous, basolaterally secreted proteins, but it did not influence the polarity of cell surface beta APP. These results demonstrate that in epithelial cells two independent mechanisms mediate the polarized trafficking of beta APP holoprotein and its major secreted derivative (APPs) and that A beta peptides are derived in part from beta APP holoprotein targeted to the cell surface by a signal that includes tyrosine 653.

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