Abstract
An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-β (Aβ) oligomers as a key factor in synaptic impairment and rodent spatial memory decline. Alterations in the α7-nicotinic acetylcholine receptor (α7-nAChR) have been implicated in AD pathology. Herein, we report that nicotine, an unselective α7-nAChR agonist, protects from morphological and synaptic impairments induced by Aβ oligomers. Interestingly, nicotine prevents both early postsynaptic impairment and late presynaptic damage induced by Aβ oligomers through the α7-nAChR/phosphatidylinositol-3-kinase (PI3K) signaling pathway. On the other hand, a cross-talk between α7-nAChR and the Wnt/β-catenin signaling pathway was revealed by the following facts: (1) nicotine stabilizes β-catenin, in a concentration-dependent manner; (2) nicotine prevents Aβ-induced loss of β-catenin through the α7-nAChR; and (3) activation of canonical Wnt/β-catenin signaling induces α7-nAChR expression. Analysis of the α7-nAChR promoter indicates that this receptor is a new Wnt target gene. Taken together, these results demonstrate that nicotine prevents memory deficits and synaptic impairment induced by Aβ oligomers. In addition, nicotine improves memory in young APP/PS1 transgenic mice before extensive amyloid deposition and senile plaque development, and also in old mice where senile plaques have already formed. Activation of the α7-nAChR/PI3K signaling pathway and its cross-talk with the Wnt signaling pathway might well be therapeutic targets for potential AD treatments.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alzheimer Disease / prevention & control*
-
Amyloid beta-Peptides / chemical synthesis
-
Amyloid beta-Peptides / toxicity*
-
Amyloid beta-Protein Precursor / genetics
-
Androstadienes / pharmacology
-
Animals
-
Bungarotoxins / pharmacology
-
Cells, Cultured
-
Dendrites / drug effects
-
Dendrites / ultrastructure
-
Disks Large Homolog 4 Protein
-
Hippocampus / cytology
-
Hippocampus / drug effects
-
Hippocampus / metabolism
-
Intracellular Signaling Peptides and Proteins / analysis
-
Maze Learning / drug effects
-
Membrane Proteins / analysis
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Neurites / ultrastructure
-
Neurons / drug effects
-
Neurons / metabolism
-
Neurons / ultrastructure
-
Nicotine / pharmacology*
-
Nicotine / therapeutic use
-
Patch-Clamp Techniques
-
Peptide Fragments / chemical synthesis
-
Peptide Fragments / toxicity*
-
Phosphatidylinositol 3-Kinases / physiology
-
Plaque, Amyloid / metabolism
-
Presenilin-1 / genetics
-
Presynaptic Terminals / drug effects
-
Presynaptic Terminals / ultrastructure
-
Rats
-
Rats, Sprague-Dawley
-
Recombinant Fusion Proteins / genetics
-
Signal Transduction
-
Synapsins / analysis
-
Wnt Proteins / physiology
-
Wnt Signaling Pathway
-
Wortmannin
-
alpha7 Nicotinic Acetylcholine Receptor / agonists
-
alpha7 Nicotinic Acetylcholine Receptor / biosynthesis
-
alpha7 Nicotinic Acetylcholine Receptor / genetics
-
alpha7 Nicotinic Acetylcholine Receptor / physiology*
-
beta Catenin / physiology
Substances
-
Amyloid beta-Peptides
-
Amyloid beta-Protein Precursor
-
Androstadienes
-
Bungarotoxins
-
CTNNB1 protein, mouse
-
Chrna7 protein, mouse
-
Chrna7 protein, rat
-
Ctnnb1 protein, rat
-
Disks Large Homolog 4 Protein
-
Dlg4 protein, rat
-
Intracellular Signaling Peptides and Proteins
-
Membrane Proteins
-
PSEN1 protein, human
-
Peptide Fragments
-
Presenilin-1
-
Recombinant Fusion Proteins
-
Synapsins
-
Wnt Proteins
-
alpha7 Nicotinic Acetylcholine Receptor
-
amyloid beta-protein (1-42)
-
beta Catenin
-
Nicotine
-
Phosphatidylinositol 3-Kinases
-
Wortmannin