Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyloid precursor protein (APP), the precursor of Abeta, has been shown to function as a cell surface receptor that mediates neuronal cell death by anti-APP antibody. The c-Jun N-terminal kinase (JNK) can mediate various neurotoxic signals, including Abeta neurotoxicity. However, the relationship of APP-mediated neurotoxicity to JNK is not clear, partly because APP cytotoxicity is Abeta independent. Here we examined whether JNK is involved in APP-mediated neuronal cell death and found that: (i) neuronal cell death by antibody-bound APP was inhibited by dominant-negative JNK, JIP-1b and SP600125, the specific inhibitor of JNK, but not by SB203580 or PD98059; (ii) constitutively active (ca) JNK caused neuronal cell death and (iii) the pharmacological profile of caJNK-mediated cell death closely coincided with that of APP-mediated cell death. Pertussis toxin (PTX) suppressed APP-mediated cell death but not caJNK-induced cell death, which was suppressed by Humanin, a newly identified neuroprotective factor which inhibits APP-mediated cytotoxicity. In the presence of PTX, the PTX-resistant mutant of Galphao, but not that of Galphai, recovered the cytotoxic action of APP. These findings demonstrate that JNK is involved in APP-mediated neuronal cell death as a downstream signal transducer of Go.
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PMID:Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death. 1256 29

The biological function of full-length amyloid-beta protein precursor (AbetaPP), the precursor of Abeta, is not fully understood. Multiple laboratories have reported that antibody binding to cell surface AbetaPP causes neuronal cell death. Here we examined whether induced dimerization of the cytoplasmic domain of AbetaPP (AbetaPPCD) triggers neuronal cell death. In neurohybrid cells expressing fusion constructs of the epidermal growth factor (EGF) receptor with AbetaPPCD (EGFR/AbetaPP hybrids), EGF drastically enhanced neuronal cell death in a manner sensitive to acetyl-l-aspartyl-l-glutamyl-l-valyl-l-aspartyl-aldehyde (Ac-DEVD-CHO; DEVD), GSH-ethyl ester (GEE), and pertussis toxin (PTX). Dominant-negative apoptosis signal-regulating kinase 1 (ASK1) blocked this neuronal cell death, but not alpha-synuclein-induced cell death. Constitutively active ASK1 (caASK1) caused DEVD/GEE-sensitive cell death in a manner resistant to PTX and sensitive to Humanin, which also suppressed neuronal cell death by EGFR/AbetaPP hybrid. ASK1 formed a complex with AbetaPPCD via JIP-1b, the c-Jun N-terminal kinase (JNK)-interacting protein. EGFR/AbetaPP hybrid-induced and caASK1-induced neuronal cell deaths were specifically blocked by SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one), a specific JNK inhibitor. Combined with our earlier study, these data indicate that dimerization of AbetaPPCD triggers ASK1/JNK-mediated neuronal cell death. We also noticed a potential role of ASK1/JNK in sustaining the activity of this mechanism after initial activation by AbetaPP, which allows for the achievement of cell death by short-term anti-AbetaPP antibody treatment. Understanding the function of AbetaPPCD and its downstream pathway should lead to effective anti-Alzheimer's disease therapeutics.
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PMID:The cytoplasmic domain of Alzheimer's amyloid-beta protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH2-terminal kinase-mediated neurotoxic signal via dimerization. 1282 23

Neuronal pathology of the brain with Alzheimer's disease (AD) is characterized by numerous depositions of amyloid-beta peptides (Abeta). Abeta binding to the 75-kDa neurotrophin receptor (p75NTR) causes neuronal cell death. Here we report that Abeta causes cell death in neuronal hybrid cells transfected with p75NTR, but not in nontransfected cells, and that p75NTR(L401K) cannot mediate Abeta neurotoxicity. We analyzed the cytotoxic pathway by transfecting pertussis toxin (PTX)-resistant G protein alpha subunits in the presence of PTX and identified that Galpha(o), but not Galpha(i), proteins are involved in p75NTR-mediated Abeta neurotoxicity. Further investigation suggested that Abeta neurotoxicity via p75NTR involved JNK, NADPH oxidase, and caspases-9/3 and was inhibited by activity-dependent neurotrophic factor, insulin-like growth factor-I, basic fibroblast growth factor, and Humanin, as observed in primary neuron cultures. Understanding the Abeta neurotoxic mechanism would contribute significantly to the development of anti-AD therapies.
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PMID:Characterization of the toxic mechanism triggered by Alzheimer's amyloid-beta peptides via p75 neurotrophin receptor in neuronal hybrid cells. 1292 30

Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
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PMID:Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. 1519 38

Humanin (HN) inhibits neuronal cell death induced by various Alzheimer's disease (AD)-related insults. It has been proposed that HN binds to a putative receptor on the cell membrane and triggers a signal transduction cascade linked to neuroprotection. Recently, it was shown that HN binds to pertussis toxin (PTX)-sensitive G protein-coupled formylpeptide receptor-like-1 molecule (FPRL-1), reduces A beta(1--42) aggregation and fibril formation, and suppresses the A beta(1--42) toxicity on mononuclear phagocytic cells [Ying, G., Iribarren, P., Zhou, Y., Gong, W., Zhang, N., Yu, Z.X., Le, Y., Cui, Y., Wang, J.M., 2004. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. Journal of Immunology 172 (11), 7078--7085.]. We here show that siRNA-mediated disruption of expression of the mouse counterpart of FPRL-1, FPR2, did not result in attenuation of HN-mediated rescue of neuronal cell death induced by AD-related insults. We simultaneously provide evidence that neuroprotection by HN in F11 cells is mediated by the STAT3 transcription factor as well as by certain tyrosine kinases. Altogether, we speculate that a receptor other than FPR2 exists that mediates HN neuroprotection in F11 neurohybrid cells.
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PMID:Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection. 1600 25