Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity
Levi M Smith1, Stephen M Strittmatter1
1Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06536.
Cold Spring Harbor Perspectives in Medicine
|December 13, 2016
Summary
Soluble amyloid-β oligomers, not plaques, drive Alzheimer's disease (AD) synaptic damage. Cellular prion protein (PrPC) binds these oligomers, initiating a toxic neuronal pathway crucial for AD pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation.
- Soluble Aβ oligomers are the primary drivers of synaptic dysfunction and neuronal loss in AD.
- Receptors mediating Aβ oligomer toxicity are critical for understanding AD pathogenesis.
Purpose of the Study:
- To identify and characterize cell-surface receptors responsible for Aβ oligomer-induced neurotoxicity in Alzheimer's disease.
- To investigate the role of cellular prion protein (PrPC) as a high-affinity binding site for toxic Aβ oligomers.
Main Methods:
- Literature review and data synthesis on Aβ binding proteins and their roles in AD.
- Analysis of signaling pathways linking Aβ-PrPC complexation to neuronal impairment.
Main Results:
- Cellular prion protein (PrPC) identified as a high-affinity receptor for soluble Aβ oligomers.
- Evidence suggests a signaling cascade initiated by Aβ oligomer binding to PrPC leads to synaptic dysfunction.
Conclusions:
- PrPC plays a significant role in mediating the neurotoxic effects of Aβ oligomers in Alzheimer's disease.
- Understanding the Aβ-PrPC interaction is key to defining the molecular basis of AD pathogenesis and developing therapeutic strategies.
Related Concept Videos
03:03Amyloid Fibrils
12.4K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
12.4K
03:03Amyloid Fibrils
6.9K
6.9K
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
4.5K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
4.5K
01:26Chemical Synapses
12.2K
Chemical synapses are specialized sites between two neurons or between a neuron and a non-neuronal cell like a muscle, glandular or sensory cell.
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
12.2K
01:26Chemical Synapses
6.2K
Chemical synapses are specialized sites between two neurons or between a neuron and a non-neuronal cell like a muscle, glandular or sensory cell.
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
6.2K