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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Nature. Author manuscript; available in PMC 2011 March 15.
Published in final edited form as:
PMCID: PMC3057871

The prion protein as a receptor for amyloid-β

Increased levels of brain amyloid-β, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer’s disease1. Increased amyloid-β can cause synaptic depression2,3, reduce the number of spine protrusions (that is, sites of synaptic contacts)4,5 and block long-term synaptic potentiation (LTP)6,7, a form of synaptic plasticity; however, the receptor through which amyloid-β produces these synaptic perturbations has remained elusive. Laurén et al.8 suggested that binding between oligomeric amyloid-β (a form of amyloid-β thought to be most active5,6,9-11) and the cellular prion protein (PrPC)8 is necessary for synaptic perturbations. Here we show that PrPC is not required for amyloid-β-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-β-mediated synaptic defects do not require PrPc.

To test whether PrPc is required for amyloid-β-induced synaptic depression we infected organotypic hippocampal slice neurons with a Sindbis virus driving expression of APPct100, a precursor of amyloid-β, which leads to increased neuronal production and secretion of amyloid-β that does not perturb the health of the neuron, as assessed electrophysiologically3. Synaptic transmission was depressed in neurons expressing APPct100, in both wild-type and Prnp−/− mouse slices (where Prnp is the gene that encodes PrPC) 24 h after infection (Fig. 1a). As previously shown for wild-type tissue3, this depression was blocked if Prnp−/− slices were maintained during the APPct100 expression period with an inhibitor of NMDA (N-methyl-d-aspartate) receptors (Fig. 1a). Thus, synaptic depression after expression of APPct100, an effect of elevated amyloid-β3, is intact in animals lacking PrPC.

Figure 1
PrPC is not required for amyloid-β-induced synaptic deficits

We next examined the effects of amyloid-β on dendritic spines, sites of excitatory synapses. Overexpression of APP4 (or exposure to oligomeric amyloid-β5) leads to loss of dendritic spines in organotypic slices prepared from wild-type animals, which can be visualized by co-expression of a cytoplasmic marker. The same APP-induced decrease of spines was seen in slices made from mice lacking PrPC (Fig. 1b). We next determined which species of amyloid-β is responsible for the observed effects. Synthetic amyloid-β(1–40) (Aβ40) peptides remain predominantly in monomeric form, and did not affect spine density (Fig. 1c). Amyloid-β(1–42) peptides (Aβ42) form oligomers, and when exogenously applied they produced a similar loss of dendritic spines in slices prepared from either wild-type or PrPC-lacking mice (Fig. 1c). Thus, the loss of dendritic spines produced by oligomeric Aβ42 exposure does not depend on PrPC.

We repeated the experiments as described in Laurén et al.8 that studied PrPC’s role in the Aβ-mediated blockade of LTP. Acutely prepared hippocampal slices from mature wild-type and Prnp−/− mice were exposed to either species of amyloid-β and LTP was induced by theta burst stimulation. We found that Aβ42 (but not Aβ40) blocked LTP irrespective of whether PrPC is present or absent (Fig. 1d).

We show that amyloid-β-induced synaptic depression, loss of dendritic spines and blockade of LTP are present in hippocampal slices prepared from PrPC-deficient animals. In line with our results, amyloid-β oligomers were shown to impair long-term memory equally in PrPC-lacking and PrPC-expressing mice12. Thus, although oligomeric amyloid-β can bind PrPC, it does not seem to be the receptor responsible for synaptic perturbations caused by oligomeric amyloid-β. Elucidation of the molecular mechanisms by which amyloid-β produces synaptic perturbations remains as a major goal in finding therapeutic treatments of Alzheimer’s disease.


C57/BL10 and C57/BL10 Prnp−/− mice were provided by M. Oldstone (Scripps Research Institute, grant AG04342). Organotypic slice cultures were infected at 7–12 days in vitro with Sindbis virus expressing APPct1003. After 24h simultaneous whole-cell paired recordings were obtained as described previously13. At 12–17 days in vitro slices were infected with Sindbis virus expressing tdTomato or APP plus tdTomato for 48 h, or infected with eGFP and incubated with 1 μM monomeric Aβ40 or oligomerized Aβ4214 for 24 h. Two-photon laser scanning images were taken of dendrites at the site of primary apical dendrite bifurcation. Spine densities were counted as described previously4. The protocol for the LTP experiments was as described in Laurén et al.8.


This work was supported by NIH grant AG032132 and the Shiley-Marcos Endowment for Alzheimer’s Disease Research to R.M.


Competing financial interests: declared none.

Arising from: J. Laurén et al. Nature 457, 1128-1132 (2009)


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