Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1

Abstract

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.