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Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233):1128-32. PubMed.
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Lauren et al. report that Aβ oligomers bind to PrPc and that the detrimental effect of Aβ on hippocampal LTP is not observed in PrPc knockout mice; PrPc presumably mediates this detrimental effect not by direct modulation of glutamate receptors but in an indirect way. There are earlier studies hinting at an association of Aβ with PrPc (e.g., Brown, 2000; Schwarze-Eicker et al., 2005) but the demonstration of a specific Aβ-binding site on PrPc opens up possibilities of exploring the role of PrPc in Alzheimer disease and the role of Aβ in prion diseases; since a high-affinity PrPc binding site for Aβ should not be accidental, it might also indicate a physiological role for Aβ. With picomolar concentrations of Aβ monomers and oligomers stimulating synaptic activity (Puzzo et al., 2008), certain species of Aβ oligomers should not be toxic under physiological conditions and their binding to PrPc may contribute to normal synaptic activity.
It has been proposed that some effects of PrPc involve an interaction of PrPc with a surface receptor and that the binding site of PrPc for this receptor overlaps segment 105-125 of PrPc (review Westergard et al., 2007). In their discussion, Lauren et al. suppose that "a putative PrPc-associated transmembrane co-receptor is likely to have a central role in Alzheimer’s disease-mediated neurodegeneration." As several publications indicate that the neurotrophin receptor p75 is essential for Alzheimer-like degeneration (e.g., review Capsoni and Cattaneo, 2006; Sotthibundhu et al., 2008), it is a candidate for such a co-receptor.
In this context, the demonstrated binding site of Aβ oligomers on PrPc (around 95-110) might support the Aβ-crosslinker-hypothesis (see Current Hypotheses), which suggests an Aβ-binding site within PrPc segment 91-123 and describes possible physiological and pathological effects of an Aβ-mediated interaction between the neurotrophin receptor p75 and PrPc, APP, and α-synuclein; the recently found Aβ-binding site within the stalk and transmembrane domain of p75 (see my recent hypothesis) would be crucial to such interactions and link Aβ-related diseases. Aggregate species of Aβ can activate p75, and available or newly formed short Aβ oligomers may crosslink p75 and PrPc. The cooperation of stimulated p75 and PrPc would activate sphingomyelinase and NADPH oxidase in a synergistic feed-forward process, and p75-Aβ-PrPc complexes could provide reactive oxygen species and elevated intracellular calcium required for components of p75 signaling. A "rapid inhibitory effect of p75(NTR) on NMDA-R currents that antagonizes TrkB-mediated NMDA-R potentiation" (Sandoval et al., 2007) should be increased by excess p75-activating Aβ and might be negatively influenced by a lack of PrPc. Excess Aβ might also induce oxidative stress and/or disturb cellular calcium homeostasis through disproportionate PrPc-receptor (and perhaps also PrPc-PrPc) crosslinking.
Brown DR. PrPSc-like prion protein peptide inhibits the function of cellular prion protein. Biochem J. 2000 Dec 1;352 Pt 2:511-8. PubMed.
Capsoni S, Cattaneo A. On the molecular basis linking Nerve Growth Factor (NGF) to Alzheimer's disease. Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):619-33. PubMed.
Puzzo D, Privitera L, Leznik E, Fà M, Staniszewski A, Palmeri A, Arancio O. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci. 2008 Dec 31;28(53):14537-45. PubMed.
Sandoval M, Sandoval R, Thomas U, Spilker C, Smalla KH, Falcon R, Marengo JJ, Calderón R, Saavedra V, Heumann R, Bronfman F, Garner CC, Gundelfinger ED, Wyneken U. Antagonistic effects of TrkB and p75(NTR) on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes. J Neurochem. 2007 Jun;101(6):1672-84. PubMed.
Schwarze-Eicker K, Keyvani K, Görtz N, Westaway D, Sachser N, Paulus W. Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging. 2005 Aug-Sep;26(8):1177-82. PubMed.
Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ. Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci. 2008 Apr 9;28(15):3941-6. PubMed.
Westergard L, Christensen HM, Harris DA. The cellular prion protein (PrP(C)): its physiological function and role in disease. Biochim Biophys Acta. 2007 Jun;1772(6):629-44. Epub 2007 Mar 2 PubMed.View all comments by Rudolf Bloechl
University of Westyern Ontario
This is outstanding work that makes a strong link for alterations in PrPc for synaptic and neuronal dysfunction. Several investigators have shown that PrPc participates in cellular signaling (see review by Linden et al., 2008); it is likely that some of these pathways may be altered/disturbed or overactivated by Aβ oligomers.
Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR. Physiology of the prion protein. Physiol Rev. 2008 Apr;88(2):673-728. PubMed.View all comments by Marco Prado
University of Kansas
This paper reports the surprising identification by expression cloning of the prion protein (PrP) as a receptor for Aβ oligomers and the synaptotoxic consequences of this interaction. There is extensive evidence in support of these findings, and if confirmed by other labs, PrP could be an important new target for AD therapeutics...so long as such compounds do not induce PrP into an aggregation-prone form called PrPsc, which causes devastating spongiform encephalopathies (e.g., CJD in humans). That would be a side effect that would be worse than the disease that one is trying to treat!
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