ABSTRACT
Amyloid-ß (Aß) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aß oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aß oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/ß-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aß-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/ß-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aß oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aß aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD.
Subject(s)
CCN Intercellular Signaling Proteins/therapeutic use , Hippocampus/drug effects , Neurons/drug effects , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/pathology , Proto-Oncogene Proteins/therapeutic use , Synapses/drug effects , Amyloid beta-Peptides/toxicity , Amyloid beta-Protein Precursor/genetics , Animals , Cells, Cultured , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Hippocampus/pathology , Hippocampus/physiology , Humans , Male , Mice , Mice, Transgenic , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/genetics , Phosphorylation/drug effects , Phosphorylation/genetics , Presenilin-1/genetics , Rats , Signal Transduction/drug effects , Signal Transduction/genetics , Synapses/genetics , Synapses/physiology , Synapses/ultrastructure , Time FactorsABSTRACT
The role of the Wnt signaling pathway during synaptic development has been well established. In the adult brain, different components of Wnt signaling are expressed, but little is known about its role in mature synapses. Emerging in vitro studies have implicated Wnt signaling in synaptic plasticity. Furthermore, activation of Wnt signaling has shown to protect against amyloid-ß-induced synaptic impairment. The present study provides the first evidence that in vivo activation of Wnt signaling improves episodic memory, increases excitatory synaptic transmission, and enhances long-term potentiation in adult wild-type mice. Moreover, the activation of Wnt signaling also rescues memory loss and improves synaptic dysfunction in APP/PS1-transgenic mice that model the amyloid pathology of Alzheimer's diseases. These findings indicate that Wnt signaling modulates cognitive function in the adult brain and could be a novel promising target for Alzheimer's disease therapy.
Subject(s)
Alzheimer Disease/metabolism , Cognition Disorders/metabolism , Cognition/physiology , Disease Models, Animal , Wnt Signaling Pathway/physiology , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Animals , Cognition Disorders/pathology , Cognition Disorders/psychology , Hippocampus/metabolism , Hippocampus/pathology , Male , Mice , Mice, Transgenic , Organ Culture TechniquesABSTRACT
During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer's disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts.
ABSTRACT
An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-ß (Aß) 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 Aß oligomers. Interestingly, nicotine prevents both early postsynaptic impairment and late presynaptic damage induced by Aß oligomers through the α7-nAChR/phosphatidylinositol-3-kinase (PI3K) signaling pathway. On the other hand, a cross-talk between α7-nAChR and the Wnt/ß-catenin signaling pathway was revealed by the following facts: (1) nicotine stabilizes ß-catenin, in a concentration-dependent manner; (2) nicotine prevents Aß-induced loss of ß-catenin through the α7-nAChR; and (3) activation of canonical Wnt/ß-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 Aß 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.
Subject(s)
Alzheimer Disease/prevention & control , Amyloid beta-Peptides/toxicity , Nicotine/pharmacology , Peptide Fragments/toxicity , alpha7 Nicotinic Acetylcholine Receptor/physiology , Amyloid beta-Peptides/chemical synthesis , 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/therapeutic use , Patch-Clamp Techniques , Peptide Fragments/chemical synthesis , 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 , beta Catenin/physiologyABSTRACT
Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulates the function of the adult nervous system. In fact, most of the key components including Wnts and Frizzled receptors are expressed in the adult brain. Wnt ligands have been implicated in the regulation of synaptic assembly as well as in neurotransmission and synaptic plasticity. Deregulation of Wnt signaling has been associated with several pathologies, and more recently has been related to neurodegenerative diseases and to mental and mood disorders. In this review, we focus our attention on the Wnt signaling cascade in postnatal life and we review in detail the presence of Wnt signaling components in pre- and postsynaptic regions. Due to the important role of Wnt proteins in wiring neural circuits, we discuss recent findings about the role of Wnt pathways both in basal spontaneous activities as well as in activity-dependent processes that underlie synaptic plasticity. Finally, we review the role of Wnt in vivo and we finish with the most recent data in literature that involves the effect of components of the Wnt signaling pathway in neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling, as well as the data that support a neuroprotective role of Wnt proteins in relation to the pathogenesis of Alzheimer's disease.