Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1
Epidemiological studies have shown that cigarette smoking increases the risk of Alzheimer disease. However, inconsistent results have been reported regarding the effects of smoking or nicotine on brain amyloid β (Aβ) deposition. In this study, we found that stimulation of the nicotinic acetylcholine...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-06-01
|
| Series: | Neuroscience Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0168010223002195 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846161688644026368 |
|---|---|
| author | Masaki Nakano Tomohiro Tsuchida Yachiyo Mitsuishi Masaki Nishimura |
| author_facet | Masaki Nakano Tomohiro Tsuchida Yachiyo Mitsuishi Masaki Nishimura |
| author_sort | Masaki Nakano |
| collection | DOAJ |
| description | Epidemiological studies have shown that cigarette smoking increases the risk of Alzheimer disease. However, inconsistent results have been reported regarding the effects of smoking or nicotine on brain amyloid β (Aβ) deposition. In this study, we found that stimulation of the nicotinic acetylcholine receptor (nAChR) increased Aβ production in mouse brains and cultured neuronal cells. nAChR activation triggered the MEK/ERK pathway, which then phosphorylated and stabilized nuclear SP1. Upregulated SP1 acted on two recognition motifs in the BACE1 gene to induce its transcription, resulting in enhanced Aβ production. Mouse brain microdialysis revealed that nAChR agonists increased Aβ levels in the interstitial fluid of the cerebral cortex but caused no delay of Aβ clearance. In vitro assays indicated that nicotine inhibited Aβ aggregation. We also found that nicotine modified the immunoreactivity of anti-Aβ antibodies, possibly through competitive inhibition and Aβ conformation changes. Using anti-Aβ antibody that was carefully selected to avoid these effects, we found that chronic nicotine treatment in Aβ precursor protein knockin mice increased the Aβ content but did not visibly change the aggregated Aβ deposition in the brain. Thus, nicotine influences brain Aβ deposition in the opposite direction, thereby increasing Aβ production and inhibiting Aβ aggregation. |
| format | Article |
| id | doaj-art-88fe2a83e4b247a2a779fcf5f11d56fb |
| institution | Kabale University |
| issn | 0168-0102 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neuroscience Research |
| spelling | doaj-art-88fe2a83e4b247a2a779fcf5f11d56fb2024-11-21T06:02:26ZengElsevierNeuroscience Research0168-01022024-06-012032841Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1Masaki Nakano0Tomohiro Tsuchida1Yachiyo Mitsuishi2Masaki Nishimura3Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, Japan; Corresponding author.Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, JapanMolecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, JapanMolecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, Japan; Department of Neurology, Yoka Municipal Hospital, Hyogo 667-8555, Japan; Corresponding author at: Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, Japan.Epidemiological studies have shown that cigarette smoking increases the risk of Alzheimer disease. However, inconsistent results have been reported regarding the effects of smoking or nicotine on brain amyloid β (Aβ) deposition. In this study, we found that stimulation of the nicotinic acetylcholine receptor (nAChR) increased Aβ production in mouse brains and cultured neuronal cells. nAChR activation triggered the MEK/ERK pathway, which then phosphorylated and stabilized nuclear SP1. Upregulated SP1 acted on two recognition motifs in the BACE1 gene to induce its transcription, resulting in enhanced Aβ production. Mouse brain microdialysis revealed that nAChR agonists increased Aβ levels in the interstitial fluid of the cerebral cortex but caused no delay of Aβ clearance. In vitro assays indicated that nicotine inhibited Aβ aggregation. We also found that nicotine modified the immunoreactivity of anti-Aβ antibodies, possibly through competitive inhibition and Aβ conformation changes. Using anti-Aβ antibody that was carefully selected to avoid these effects, we found that chronic nicotine treatment in Aβ precursor protein knockin mice increased the Aβ content but did not visibly change the aggregated Aβ deposition in the brain. Thus, nicotine influences brain Aβ deposition in the opposite direction, thereby increasing Aβ production and inhibiting Aβ aggregation.http://www.sciencedirect.com/science/article/pii/S0168010223002195Alzheimer's diseaseNicotinic acetylcholine receptorAβBACE1SP1Nicotine |
| spellingShingle | Masaki Nakano Tomohiro Tsuchida Yachiyo Mitsuishi Masaki Nishimura Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1 Neuroscience Research Alzheimer's disease Nicotinic acetylcholine receptor Aβ BACE1 SP1 Nicotine |
| title | Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1 |
| title_full | Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1 |
| title_fullStr | Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1 |
| title_full_unstemmed | Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1 |
| title_short | Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1 |
| title_sort | nicotinic acetylcholine receptor activation induces bace1 transcription via the phosphorylation and stabilization of nuclear sp1 |
| topic | Alzheimer's disease Nicotinic acetylcholine receptor Aβ BACE1 SP1 Nicotine |
| url | http://www.sciencedirect.com/science/article/pii/S0168010223002195 |
| work_keys_str_mv | AT masakinakano nicotinicacetylcholinereceptoractivationinducesbace1transcriptionviathephosphorylationandstabilizationofnuclearsp1 AT tomohirotsuchida nicotinicacetylcholinereceptoractivationinducesbace1transcriptionviathephosphorylationandstabilizationofnuclearsp1 AT yachiyomitsuishi nicotinicacetylcholinereceptoractivationinducesbace1transcriptionviathephosphorylationandstabilizationofnuclearsp1 AT masakinishimura nicotinicacetylcholinereceptoractivationinducesbace1transcriptionviathephosphorylationandstabilizationofnuclearsp1 |