Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Open accessAbstract
A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-beta peptide of 40-42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-beta have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-beta oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-beta 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-beta oligomers on neurons-one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrP(C)) as an amyloid-beta-oligomer receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-beta oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-beta-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-beta. Thus, PrP(C) is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.
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Aβ oligomers bind to α7 nicotinic acetylcholine receptors (α7 nAChRs) and to metabotropic glutamate receptors, in particular mGluR5.
“Aβ binds to α7 nicotinic acetylcholine receptors (α7 nAChRs) and to metabotropic glutamate receptors, in particular mGluR5 [31–33].”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [33]
A genome-wide association study identified PrPC as a potential high-affinity receptor for oAβ.
“A genome-wide association study (GWAS) identified PrPC as a potential high-affinity receptor for oAβ [87].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [87]
oAβ, especially high-molecular weight oligomers, preferentially bind to PrPC within an N-terminal 95-111aa segment.
“Subsequent studies showed that oAβ, especially high-molecular weight oligomers [88], preferentially bind to PrPC within an N-terminal 95-111aa segment [87].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [87]
Oligomer binding is significantly reduced in PrPC knock-out cells.
“oligomer binding is significantly reduced in PrPC knock-out cells (Lauren et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lauren et al., 2009
Aβ oligomers bind with nanomolar affinity to cellular prion protein (PrPC), and anti-PrP antibodies reduce oligomer binding to neurons and rescue synaptic plasticity.
“Aβ oligomers bind with nanomolar affinity to cellular prion protein (PrPC) and that anti-PrP antibodies reduce oligomer binding to neurons and rescue synaptic plasticity (Lauren et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lauren et al., 2009
Knocking down NMDARs or PrPC, or adding antibodies against their extracellular domains, blocks the accumulation of ADDL clusters at synapses.
“explaining the finding that knocking-down these proteins or adding antibodies against their extracellular domains blocks the accumulation of ADDL clusters (“hotspots”) at synapses (De Felice et al., 2007; Decker et al., 2010a; Lauren et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lauren et al., 2009
PrPC binds synthetic Aβ oligomers with high affinity and plays a role in oligomer-mediated inhibition of long-term potentiation.
“PrPC binds synthetic Aβ oligomers with high affinity and plays a role in the oligomer-mediated inhibition of LTP (17).”
From Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein (2010) · cites this paper as [17]
Lauren et al. reported that PrPC mediates Aβ oligomer-induced hippocampal synaptic plasticity impairment.
“In an elegant study Lauren et al. (17) reported that PrPC mediates the Aβ oligomer-induced hippocampal synaptic plasticity impairment.”
From Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein (2010) · cites this paper as [17]
Aβ1-42 oligomers prepared at 22 °C according to the Lauren et al. procedure impaired recognition memory in both Prnp +/+ and Prnp 0/0 mice.
“The 22 °C-Aβ oligomers impaired recognition memory in both Prnp +/+ and Prnp 0/0 mice (Fig. 4C).”
From Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein (2010) · cites this paper as [17]
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- Authors
- Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., & Strittmatter, S. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Strittmatter, Stephen M.
- Venue
- Nature
- Published
- 2009-02
- Volume
- 457
- Issue
- 7233
- Pages
- 1128-1132
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2748841
- OpenAlex
- W2171526610
- Cited by
- 1,560
- References
- 37
- Citations by year
- 2026: 46 · 2025: 45 · 2024: 50 · 2023: 52 · 2022: 87 · 2021: 82 · 2020: 85 · 2019: 71 · 2018: 108 · 2017: 117 · 2016: 103 · 2015: 98 · 2014: 104 · 2013: 116 · 2012: 119
- FWCI
- 87.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Public Health Service (5T32GN07205)
- National Institute on Drug Abuse (P30DA018343)
- National Institute of Neurological Disorders and Stroke (R01NS042304, R01NS039962, R37NS033020)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cellular prion protein, amyloid-beta oligomers, Alzheimer's disease, synaptic plasticity, long-term potentiation, cell surface receptors, lipid rafts, hippocampus, anti-PrP antibodies, prion disease, expression cloning, neurotoxicity, spatial memory, neuroprotection, neurodegeneration
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Chlorocebus aethiops, Hippocampus, Humans, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Peptide Fragments, Prions, Protein Binding, Receptors, Cell Surface, Synapses, Amyloid beta-Peptides, Long-Term Potentiation, COS Cells, Mice, Amyloid Precursor Protein Secretases, Protein Multimerization
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