(I) Pharmacological profiling of a novel modulator of the α7 nicotinic receptor: Blockade of a toxic acetylcholinesterase-derived peptide increased in Alzheimer brains
| Autor: | Antoine-Scott Badin, Susan A. Greenfield, Catherine Heffner, Clive W. Coen, Cristina Tormo-Garcia, Paul Morrill, Henry Tu, Sara Garcia-Ratés, Gwenael Pottiez |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
alpha7 Nicotinic Acetylcholine Receptor Amyloid beta Cell Survival Allosteric regulation Peptide tau Proteins Neuroprotection PC12 Cells Peptides Cyclic Tissue Culture Techniques 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Alzheimer Disease medicine Galantamine Animals Humans Pharmacology chemistry.chemical_classification Amyloid beta-Peptides biology P3 peptide Brain Hydrogen Peroxide medicine.disease Acetylcholinesterase Peptide Fragments Rats 030104 developmental biology Neuroprotective Agents chemistry biology.protein Cholinesterase Inhibitors Alzheimer's disease Neuroscience 030217 neurology & neurosurgery Allosteric Site Biomarkers medicine.drug |
| Zdroj: | Neuropharmacology. 105 |
| ISSN: | 1873-7064 |
| Popis: | The primary cause of Alzheimer's disease is unlikely to be the much studied markers amyloid beta or tau. Their widespread distribution throughout the brain does not account for the specific identity and deep subcortical location of the primarily vulnerable neurons. Moreover an unusual and intriguing feature of these neurons is that, despite their diverse transmitters, they all contain acetylcholinesterase. Here we show for the first time that (1) a peptide derived from acetylcholinesterase, with independent trophic functions that turn toxic in maturity, is significantly raised in the Alzheimer midbrain and cerebrospinal fluid; (2) a synthetic version of this peptide enhances calcium influx and eventual production of amyloid beta and tau phosphorylation via an allosteric site on the α7 nicotinic receptor; (3) a synthetic cyclic version of this peptide is neuroprotective against the toxicity not only of its linear counterpart but also of amyloid beta, thereby opening up the prospect of a novel therapeutic approach. |
| Databáze: | OpenAIRE |
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