Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers

By J. Lauren, D. Gimbel, H. Nygaard, John W. Gilbert, S. Strittmatter. Nature, 2009

1,466 citations recorded by the source corpus.

A pathological hallmark of Alzheimer’s disease is an accumulation of insoluble plaque containing the amyloid-β peptide of 40–42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-β have been recognized to be early and key intermediates in Alzheimer’s-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-β oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-β oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer’s disease brain. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-β oligomers on neurons—one that is central to the pathophysiological process in Alzheimer’s disease. Here we identify the cellular prion protein (PrPC) as an amyloid-β-oligomer receptor by expression cloning. Amyloid-β oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrPC is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e7555c5531d5682ca794b24f0cc9325b36861aa5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. D. Selkoe
2. L. Ittner
3. J. Götz
4. Mark P. Mattson
5. Urmi Sengupta
6. D. Walsh
7. A. Nilson
8. R. Kayed

In Physiology

1. D. Selkoe
2. L. Ittner
3. D. Walsh
4. J. Götz
5. Nina E. Shepardson
6. Mark P. Mattson
7. R. Kayed
8. M. Jin

Citations in the corpus

• Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease (2011, background): “Although there might be a single receptor that mediates amyloid-β toxicity at the postsynaptic compartment, it seems more likely that several postsynaptic receptors are involved, such as prion proteins, α7-nicotinergic receptors, metabotropic glutamate receptors (mGluRs) and, in particular, NMDAR”
• Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration (2011, background): “S4A), in accord with evidence that the neurotoxicity of synthetic Aβ (at much higher concentrations) requires the maturation of neurons in vitro (12, 13).”
• The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy (2016, background): “These oligomers were also shown to bind to the PrPc and lead to a series of events disrupting synaptic function in hippocampal neurons (Freir et al., 2011; Lauren et al., 2009; Um et al., 2012).”
• Protein aggregation diseases: pathogenicity and therapeutic perspectives (2010, background): “Intriguingly, a recent study has claimed that endogenous PrP C may be one of the cell surface receptors mediating synaptic dysfunction associated with oligomeric A&beta”