High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer's amyloid β peptide (Aβ)

Haugabook, Sharie J.; Yager, Debra; Eckman, Elizabeth A.; Golde, Todd E.; Younkin, Steven G.; Eckman, Christopher B.

doi:10.1016/s0165-0270(01)00388-0

Cited by 40 publications

(36 citation statements)

References 28 publications

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“…As additional confirmation of PA-mediated iA␤ accumulation, we repeated the experiments with the CNS-derived H4 cell line transfected with wild-type APP (29). Similar to the results obtained with SH-SY5Y-APP cells, treatment of H4-APP cells with 100 M PA for 48 h produced significant increases in both eA␤ and iA␤ levels ( Fig.…”

Section: Pa Treatmentsupporting

confidence: 67%

Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

Pacheco‐Quinto

Eckman

2013

Journal of Biological Chemistry

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Background: Endothelin-converting enzymes (ECEs) degrade ␤-amyloid (A␤) peptide. Results: ECE inhibition produces, in addition to extracellular A␤ accumulation, intracellular A␤ accumulation within endosomal/lysosomal and autophagic vesicles. Conclusion: An intracellular pool of A␤ is regulated by ECE activity at the sites of production. Significance: ECE dysfunction may cause intraneuronal A␤ accumulation, which is associated with neurotoxicity early in AD progression.

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Section: Pa Treatmentsupporting

confidence: 67%

Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

Pacheco‐Quinto

Eckman

2013

Journal of Biological Chemistry

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“…The human neuroblastoma cell line SK-N-SH is able to produce both Aβ1-40 and Aβ1-42 (Haugabook et al, 2001). In our experiments, we found that Aβ1-42 was produced in the medium to about 0.48 pg/µg DNA.…”

Section: Discussionsupporting

confidence: 47%

“…SK-N-SH cells were found to be able to secrete Aβ into the medium (Haugabook et al, 2001). Also, we wanted to investigate whether these substances are able to increase the intracellular cAMP level in SK-N-SH cells to clarify the possible mechanism responsible for the induction of the activity of NEP and ACE.…”

Section: Introductionmentioning

confidence: 99%

Influence of Selected Natural Products on Neutral Endopeptidase Activity and β-Amyloid Production in SK-N-SH Cells

Ayoub

Melzig

2008

Pharmaceutical Biology

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Neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) belong to the major Aβ-degrading enzymes. We currently demonstrate that apigenin, luteolin, and curcumin are able to enhance the activity of NEP and ACE. In this research, we examined the influence of these substances on the amount of endogenously produced and secreted Aβ of neuroblastoma cells. We found that treatment of the cells for 72 h with apigenin, luteolin, and curcumin decreases the endogenous Aβ1-42 level of SK-N-SH cells significantly, which indicates that the upregulation of both NEP and ACE activity leads to a decrease of Aβ in the medium. Furthermore, we showed that all of these substances are able to increase the intracellular cAMP level, which verifies our previous supposition that the enhancement of cellular NEP activity is correlated with an increase of cAMP level.

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“…A␤ ELISA Analysis-Sandwich ELISAs for the detection of human A␤ and A␤ were performed as described previously (29 Gene Expression Analysis-Cell RNA was prepared using the RNeasy extraction kit (Qiagen, Crawley, UK) according to the manufacturer's protocol. RNA was treated with DNase I (Invitrogen), and cDNA was prepared using the iScript cDNA kit (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

The Transcriptionally Active Amyloid Precursor Protein (APP) Intracellular Domain Is Preferentially Produced from the 695 Isoform of APP in a β-Secretase-dependent Pathway

Belyaev¹,

Kellett²,

Beckett

et al. 2010

Journal of Biological Chemistry

180

177

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Amyloidogenic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases generates several biologically active products, including amyloid-␤ (A␤) and the APP intracellular domain (AICD). AICD regulates transcription of several neuronal genes, especially the A␤-degrading enzyme, neprilysin (NEP). APP exists in several alternatively spliced isoforms, APP 695 , APP 751 , and APP 770 . We have examined whether each isoform can contribute to AICD generation and hence up-regulation of NEP expression. Using SH-SY5Y neuronal cells stably expressing each of the APP isoforms, we observed that only APP 695 up-regulated nuclear AICD levels (9-fold) and NEP expression (6-fold). A characteristic feature of Alzheimer disease (AD) 5 is the presence in the brain of extracellular amyloid plaques composed of the amyloid ␤-peptide (principally A␤ 1-40 and A␤ 1-42 ), which is derived from the transmembrane amyloid precursor protein (APP). Hence, for almost two decades, the amyloid cascade hypothesis (1, 2) has driven much AD research with a focus on the prevention of A␤ accumulation or the enhancement of its clearance as primary therapeutic strategies. In the amyloidogenic pathway of APP metabolism, A␤ is formed through the sequential actions of ␤-and ␥-secretases, whereas the non-amyloidogenic ␣-secretase pathway precludes A␤ formation. Enzymic clearance of A␤ is mediated by several enzymes, of which the metallopeptidase neprilysin (NEP) is a key contributor, and up-regulation of A␤-degrading enzymes is a potential therapeutic strategy (3, 4).Three major isoforms of APP are produced due to the alternative splicing of exons 7 and 8, which encode a 56-amino acid Kunitz-type proteinase inhibitor (KPI) domain and a 19-amino acid domain that shares sequence identity with the OX-2 antigen of thymus-derived lymphoid cells, respectively (5). The longest isoform, APP 770 , contains both the KPI and the OX-2 domains, whereas APP 751 contains only the KPI domain. The shortest isoform, APP 695 , lacks both domains. In the brain, APP 695 is expressed at high levels, and the APP 751/770 isoforms are expressed at significantly lower levels, although there are regional differences, and it has been suggested that the balance between the KPI-and non-KPI-containing isoforms may be an important factor influencing A␤ deposition (6). In the AD brain (7-9) and in response to N-methyl-Daspartate (NMDA) receptor stimulation (10, 11), there is an increase in the proportion of KPI-to non-KPI-containing isoforms of APP. This has led to the suggestion that the KPIcontaining isoforms of APP can exert important neuroprotective functions, and thus their up-regulation in the AD brain or in response to excitotoxic insult may be to protect against further neuronal loss (12, 13).A major unmet scientific need in the AD field is still to understand the normal function of APP (14). An added complexity is whether the different APP isoforms have similar or distinct localizations, metabolism, and roles (15). A long standing enigma in APP biology has additi...

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High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer's amyloid β peptide (Aβ)

Cited by 40 publications

References 28 publications

Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

Influence of Selected Natural Products on Neutral Endopeptidase Activity and β-Amyloid Production in SK-N-SH Cells

The Transcriptionally Active Amyloid Precursor Protein (APP) Intracellular Domain Is Preferentially Produced from the 695 Isoform of APP in a β-Secretase-dependent Pathway

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