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Comment
. 2010 Aug 12;466(7308):E3-4; discussion E4-5.
doi: 10.1038/nature09217.

The prion protein as a receptor for amyloid-beta

Helmut W Kessels  1 , Louis N Nguyen, Sadegh Nabavi, Roberto Malinow
Affiliations
Comment

The prion protein as a receptor for amyloid-beta

Helmut W Kessels et al. Nature. .

Abstract

Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Laurén et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c).

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Figures

Figure 1
Figure 1. PrPC is not required for amyloid-β-induced synaptic deficits
a, Depression of whole-cell recorded synaptic AMPA receptor currents in a CA1 hippocampal neuron infected with Sindbis virus expressing APPct100 (grey bars) compared to a simultaneously recorded non-infected neuron (white bars) in wild-type (WT; 73 ± 8%, n = 18, P = 0.02) and Prnp−/− slices (59 ± 9%, n = 25, P = 0.002). Incubation of slices with 100 μM d-amino-phosphono-valeric acid (d-APV) during APPct100 expression abolished synaptic depression in WT (98 ± 11%, n = 12, P = 0.6) and Prnp−/− slices (105 ± 13%, n = 13, P = 0.6). EPSC, excitatory postsynaptic current. b, Decreased spine density by APP expression in WT (n = 14 APP expressing, n = 9 control dendrites, P = 0.03) and Prnp−/− slices (n = 13 APP expressing, n = 9 control dendrites, P = 0.01). Representative images of a dendrite in conditions as indicated. c, Spine loss in PrPC-deficient hippocampal slices is specific to incubation with oligomeric amyloid-β. Aβ42, but not Aβ40, preparation produced high molecular mass oligomers, as indicated by western blot analysis. WT and Prnp−/− slices were incubated with no peptide (ctrl: WT, n = 22; Prnp−/−, n = 22), with Aβ40 (WT, n = 22; Prnp−/−, n = 20), or with Aβ42 (WT, n = 22; Prnp−/−, n = 22) at 1 μM peptide concentration for 24 h, and spine densities were analysed blind to the experimenter. Spine densities were unaffected by monomeric amyloid-β incubation (WT, P = 0.4; Prnp−/−, P = 0.9), but significantly reduced by incubation with oligomeric amyloid-β (WT, P = 0.02; Prnp−/−, P = 0.03). Representative images of a dendrite in conditions as indicated. d, Oligomeric Aβ42 blocks LTP independent of the PrPC. Hippocampal slices were isolated from 2–3-month-old WT or Prnp−/− mice. Field excitatory postsynaptic potentials (fEPSPs) were measured on two independent pathways in the presence of either 500 nM Aβ40 or 500 nM Aβ42. A control pathway (open circles) was recorded while theta burst stimulation (ten 100-Hz four shock bursts with 200-ms interburst intervals, arrow) was delivered to the second pathway (filled circles) after recording a 15 min baseline. LTP was significantly depressed by Aβ42 compared with Aβ40 in both WT (P < 0.001) and Prnp−/− slices (P < 0.001). When compared to their corresponding control pathway, LTP was successfully induced in WT (P < 0.05) and Prnp−/− slices (P < 0.05) treated with monomers. Block of LTP was found in both WT (P > 0.05) and Prnp−/− (P > 0.05) oligomer-treated slices when compared to their corresponding control pathway. Statistical comparisons (P) were performed using paired (a) or non-paired (b–d) two-tailed Student’s t-test of log-transformed data. All error bars, s.e.m.; asterisk indicates P < 0.05.
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