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Transcriptome Profile of Nicotinic Receptor-Linked Sensitization of Beta Amyloid Neurotoxicity.

ABSTRACT: Understanding the specific gene changes underlying the prodromic stages of Alzheimer's disease pathogenesis will aid the development of new, targeted therapeutic strategies for this neurodegenerative disorder. Here, we employed RNA-sequencing to analyze global differential gene expression in a defined model nerve cell line expressing ?4?2 nicotinic receptors (nAChRs), high-affinity targets for beta amyloid (A?). The nAChR-expressing neuronal cells were treated with nanomolar A?1-42 to gain insights into the molecular mechanisms underlying A?-induced neurotoxicity in the presence of this sensitizing target receptor. We identified 15 genes (out of 15,336) that were differentially expressed upon receptor-linked A? treatment. Genes up-regulated with A? treatment were associated with calcium signaling and axonal vesicle transport (including the ?4 nAChR subunit, the calcineurin regulator RCAN3, and KIF1C of the kinesin family). Downregulated genes were associated with metabolic, apoptotic or DNA repair pathways (including APBA3, PARP1 and RAB11). Validation of the differential expression was performed via qRT-PCR and immunoblot analysis in the defined model nerve cell line and primary mouse neurons. Further verification was performed using immunocytochemistry. In conclusion, we identified apparent changes in gene expression on A? treatment in the presence of the sensitizing nAChRs, linked to early-stage A?-induced neurotoxicity, which may represent novel therapeutic targets.

SUBMITTER: Arora K

PROVIDER: S-EPMC7105468 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Transcriptome Profile of Nicotinic Receptor-Linked Sensitization of Beta Amyloid Neurotoxicity.

Arora Komal K Belcaid Mahdi M Lantz Megan J MJ Taketa Ruth R Nichols Robert A RA

Scientific reports 20200330 1

Understanding the specific gene changes underlying the prodromic stages of Alzheimer's disease pathogenesis will aid the development of new, targeted therapeutic strategies for this neurodegenerative disorder. Here, we employed RNA-sequencing to analyze global differential gene expression in a defined model nerve cell line expressing α4β2 nicotinic receptors (nAChRs), high-affinity targets for beta amyloid (Aβ). The nAChR-expressing neuronal cells were treated with nanomolar Aβ<sub>1-42</sub> to ...[more]

PMID: 32231242

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Project description:Amyloid ? peptide (A?) is a key player in the development of Alzheimer's disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by ?7 nicotinic receptors has been shown to be affected by A? soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric A?1-40 and A?1-42 on human ?7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV) revealed that in the presence of A? ?7 undergoes concentration-dependent conformational changes. Exposure of ?7 to 100 pM A? changes CrV KD towards that of the desensitized state. However, ?7 is still reactive to high carbamylcholine (Carb) concentrations. These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both A? and Carb. At 100 nM A?, ?7 adopts a resting-state-like structure which does not respond to Carb, suggesting stabilization of ?7 in a blocked state. In real time, we found that A? is capable of eliciting ?7 channel activity either in the absence or presence of the positive allosteric modulator (PAM) PNU-120596. Activation by A? is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high A? concentrations, the mean duration of activation episodes elicited by ACh in the presence of PNU-120596 is significantly reduced, an effect compatible with slow open-channel block. We conclude that A? directly affects ?7 function by acting as an agonist and a negative modulator. Whereas the capability of low concentrations of A? to activate ?7 could be beneficial, the reduced ?7 activity in the presence of higher A? concentrations or its long exposure may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD.

Dataset Information

Transcriptome Profile of Nicotinic Receptor-Linked Sensitization of Beta Amyloid Neurotoxicity.

Publications

Transcriptome Profile of Nicotinic Receptor-Linked Sensitization of Beta Amyloid Neurotoxicity.

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