NDLI: Nicotinic Acetylcholine Receptors Sensitize a MAPK-linked Toxicity Pathway on Prolonged Exposure to β-Amyloid

Content Provider	Journal of Biological Chemistry (JBC)
Author	Arora, Komal Cheng, Justin Nichols, Robert A.
Abstract	Among putative downstream synaptic targets of β-amyloid (Aβ) are signaling molecules involved in synaptic function, memory formation and cognition, such as the MAP kinases, MKPs, CaMKII, CREB, Fyn, and Tau. Here, we assessed the activation and interaction of signaling pathways upon prolonged exposure to Aβ in model nerve cells expressing nicotinic acetylcholine receptors (nAChRs). Our goal was to characterize the steps underlying sensitization of the nerve cells to neurotoxicity when Aβ-target receptors are present. Of particular focus was the connection of the activated signaling molecules to oxidative stress. Differentiated neuroblastoma cells expressing mouse α4β2-nAChRs were exposed to Aβ1–42 for intervals from 30 min to 3 days. The cells and cell-derived protein extracts were then probed for activation of signaling pathway molecules (ERK, JNK, CaMKII, CREB, MARCKS, Fyn, tau). Our results show substantial, progressive activation of ERK in response to nanomolar Aβ exposure, starting at the earliest time point. Increased ERK activation was followed by JNK activation as well as an increased expression of PHF-tau, paralleled by increased levels of reactive oxygen species (ROS). The impact of prolonged Aβ on the levels of pERK, pJNK, and ROS was attenuated by MEK-selective and JNK-selective inhibitors. In addition, the MEK inhibitor as well as a JNK inhibitor attenuated Aβ-induced nuclear fragmentation, which followed the changes in ROS levels. These results demonstrate that the presence of nAChRs sensitizes neurons to the neurotoxic action of Aβ through the timed activation of discrete intracellular signaling molecules, suggesting pathways involved in the early stages of Alzheimer disease.
Related Links	http://www.jbc.org/content/290/35/21409.abstract
Ending Page	21420
Starting Page	21409
Page Count	12
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	35
Volume Number	290
DOI	10.1074/jbc.M114.634162
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2015-08-28
Access Restriction	Open
Subject Keyword	Amyloid-beta (AB) C-Jun N-terminal kinase (JNK) Extracellular-signal-regulated kinase (ERK) Mitogen-activated protein kinase (MAPK) Nicotinic acetylcholine receptors (nAChR) Neurobiology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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