15 research outputs found
Upregulation of α7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides
BACKGROUND: The alpha-7 nicotinic acetylcholine receptor (alpha7-nAChR) is well known as a potent calcium ionophore that, in the brain, has been implicated in excitotoxicity and hence in the underlying mechanisms of neurodegenerative disorders such as Alzheimer's disease. Previous research implied that the activity of this receptor may be modified by exposure to a peptide fragment derived from the C-terminal region of the enzyme acetylcholinesterase. This investigation was undertaken to determine if the functional changes observed could be attributed to peptide binding interaction with the alpha7-nAChR, or peptide modulation of receptor expression. METHODOLOGY/PRINCIPAL FINDINGS: This study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the alpha7-nAChR, but also alter receptor binding properties for its familiar ligands, including the alternative endogenous agonist choline. Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane. CONCLUSIONS/SIGNIFICANCE: The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain. Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration
Upregulation of α7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides
BACKGROUND: The alpha-7 nicotinic acetylcholine receptor (alpha7-nAChR) is well known as a potent calcium ionophore that, in the brain, has been implicated in excitotoxicity and hence in the underlying mechanisms of neurodegenerative disorders such as Alzheimer's disease. Previous research implied that the activity of this receptor may be modified by exposure to a peptide fragment derived from the C-terminal region of the enzyme acetylcholinesterase. This investigation was undertaken to determine if the functional changes observed could be attributed to peptide binding interaction with the alpha7-nAChR, or peptide modulation of receptor expression. METHODOLOGY/PRINCIPAL FINDINGS: This study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the alpha7-nAChR, but also alter receptor binding properties for its familiar ligands, including the alternative endogenous agonist choline. Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane. CONCLUSIONS/SIGNIFICANCE: The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain. Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration
Additive Toxicity of β-Amyloid by a Novel Bioactive Peptide In Vitro: Possible Implications for Alzheimer’s Disease
Spill-in counts in the quantification of 18F-florbetapir on Aβ-negative subjects: the effect of including white matter in the reference region
Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease
Inhibition of Chemokine (C-C Motif) Receptor 7 Sialylation Suppresses CCL19-Stimulated Proliferation, Invasion and Anti-Anoikis
One-Compound-Multi-Targets at Amyloid β Cascade Offered By Bis(7)-Cognitin, a Novel Anti-Alzheimer’s Dimer
Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. The neuropathological hallmarks of AD are senile plaques, which are extracellular deposits predominantly composed of fibrillar amyloid β peptide (Aβ), and intracellular neurofibrillary tangles composed of filamentous aggregates called paired helical filaments of hyperphosphorylated tau protein. Aβ is proposed to play a key role in the pathogenesis of AD. Therefore, treatments targeting the biosynthesis, oligomerization/aggregation, and toxicity of Aβ are likely to be the promising disease-modifying therapeutics. Bis(7)-Cognitin, one of our promising anti-Alzheimer's dimers, has previously been shown to possess potent acetylcholinesterase (AChE) inhibition, memory-enhancement, and neuroprotection against several stimuli that go beyond the inhibition of AChE. Our recent studies have further demonstrated that bis(7)-Cognitin exerts profound neuroprotective effects by targeting the multiple stages of the Aβ pathological cascade of AD, i.e. the biosynthesis, oligomerization/aggregation and toxicity of Aβ. These findings may offer not only a new and clinically significant modality as to how the agent exerts neuroprotective effects, but also a novel direction to rationally develop one-compound-multi-targets drugs for the prevention and treatment of AD, even of other neurodegenerative diseases.Department of Applied Biology and Chemical Technolog