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. 2012 Sep 1;6(4):359–363. doi: 10.4161/pri.20675

The P’s and Q’s of cellular PrP-Aβ interactions

David Westaway 1,2,3,*, Jack H Jhamandas 1,*
PMCID: PMC3609064  PMID: 22874673

Abstract

Prion disease research has opened up the “black-box” of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrPC, is converted to a disease-associated, β-sheet enriched isoform called PrPSc. In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target,1 but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrPSc in prion diseases.2,3 Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions,4 and, with a neuron-to-neuron ‘spreading’ also reported for pathologic forms of other misfolded proteins, Tau5,6 and α-synuclein in the case of Parkinson Disease.7,8 The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of “prionoids”9, and lies outside the scope of this particular review where we will focus upon PrPC. From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrPC,10 (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrPC (Fig. 1) (3) similar lipid raft environments for PrPC and APP processing machinery,11-13 and perhaps in consequence, overlaps in repertoire of the PrPC and APP protein interactors (“interactomes”),14,15 and (4) rare kindreds with mixed AD and prion pathologies.16 Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.

Keywords: APP, Alzheimer disease, BSE, Creutzfeldt-Jakob disease, GPI-anchored glycoprotein, amyloid, prionoids, prions, protein misfolding

Panoplies of Partners

PrPC is a small GPI-anchored glycoprotein of about 210 residues. In 2009 it was identified as binding oligomeric (soluble multimeric) forms of Aβ.10 Aβ attenuated hippocampal activity in brain slices from two lines of PrP null (Prnp00) mice,10 suggesting a “pro-pathogenic” action for PrPC in AD. This is all well and good but prior work had already shown that PrPC binds to a dizzying array of entities, these including proteins, membranes, glycosaminoglycans and transition metals.17,18 Just to account for how PrP can interact with so many membrane receptors, a special hypothesis has been created to posit PrPC-enriched sub-domains of the plasma membrane organized for the purpose of signaling.19 A similar situation already existed for the relaxed binding properties of Aβ, where a panoply of interacting partners includes RAGE receptors, NMDA receptors, glutamate receptors, nicotinic acetylcholine receptors, insulin receptors, etc.20 The list of former partners on both sides of the family has created concern for the longevity of the new union, and certainly hydrophobic aspects of PrP and the multiplicity of physiochemical forms of Aβ might go some way to explaining the situation. In one view, PrPC has an intrinsic range to its binding partners, as it has been proposed to dock different types of amyloid assembly.21 On the plus side of the ledger, PrP-like molecules have been excluded as interacting with oligomeric forms of Aβ 10, biological endpoints are not attained when the PrP gene is deleted, and some studies have now begun to assess combinations with the additional binding partner Cu(II) to create more informative models of pathogenesis.22 It is also possible that interactions with low specificity and hence a low Kd might nonetheless come to predominate and determine phenotypic outputs. This situation might apply in the intact CNS under conditions wherein the process of Aβ aggregation (in the absence of adequate clearance mechanisms) leads to levels of this peptide transitioning from the nanomolar range23-25 to attain supranormal concentrations.

Pleiomorphism in Aβ and PrPC

Adding to difficulty of comparing results between labs is the variety of methods used for prepare oligomeric Aβ (as reviewed recently,26), the chemical heterogeneity on Aβ arising from different N- and C-terminal cleavage sites, and the presence or absence of N-terminal cyclization reactions.27 The situation is no simpler for PrP, where the different Aβ binding sites reported in the literature10,28 beyond the full-length anchored molecule must necessarily lie within at least three secreted forms and one membrane-anchored form, each with potential for a distinct biological consequence upon Aβ-docking (Fig. 1). Future studies moving from molecule to whole animal endpoints will have to get to grips with these heterogeneities.

graphic file with name prio-6-359-g1.jpg

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Figure 1. PrP fragments and Aβ binding sites. A schematic of PrPC (colored) and its endoproteolytic products (open boxes with shadows) is presented, along with the positions of oligomeric Aβ binding sites (boxes). The coordinates of N- and C- termini of protein species are indicated by numbering and by dashed lines. Mapped binding sites are, from top to bottom, from the data of Lauren et al., Chen et al., Freier et al. Data from Chen et al. and from Freier et al. derive from human PrP binding studies and the human PrP coordinates have been converted to the mouse PrP numbering scheme. A consensus minimal region from the central site and the N-terminal 23–27 site are both positioned on PrP proteolytic fragments (green boxes). The site accounting for ~75% of binding is inferred from the data of Freier et al., although the authors note that sequences within residues 23–89 (mouse numbering scheme) modulate the high affinity interaction.

Proteolytic Pathways

Processing events of APP by pathologic (β- plus γ-cleavage) and non-pathologic (α- plus γ-cleavage) endoproteolytic pathways are well known, and mediated by defined secretase enzymes. The endoproteases involved in PrP cleavage are a little more controversial than those for APP29-31 but irrespective of whether or not PrPC is subject to cleavage by any endoprotease that also acts upon APP, there is nonetheless a curious parallel between the alternative cleavage pathways that can process APP and PrPC.32 Thus β-like cleavage of PrPC to generate a C2-PrP fragment is potentially pathologic, as C2 PrP can form PrPSc, and, alternatively, an α-like cleavage to generate C1-PrP is protective with regards to prion misfolding since C1-PrP cannot form PrPSc.33, 34 C2-PrP is seen readily in prion infections and less abundant in normal brain whereas C1 is readily detected in normal brain samples.35,36 The concept of a “switch” or decision point hinging upon processing of PrP to N1/C1 vs. to N2/C2 (and hence the relative stoichiometries of these fragments) may also have validity when one considers cellular insults other than prion infections. For example, upon exposure to staurosporine or an ischemia paradigm the N1 fragment of PrP is noted as being protective37 while C1-PrP, but not C2-PrP, has a pro-apoptotic effect.38 Extending this discussion to the context of AD it is striking that the 95–105 Aβ binding site for PrPC reported by Lauren et al. lies in between the C2 and C1 N-termini. Thus Aβ binding could either alter the balance of proteolytic events affecting PrP, or could alter signaling events by modulating membrane-tethered vs. secreted PrP fragments. Indeed, in recent studies N1 PrP is reported to abrogate aspects of Aβ-toxicity.39 A last consideration falling within the envelope of proteolytic pathways goes beyond a passive role for PrP as a substrate to consider a more active relationship with proteases. Thus one lab has proposed that PrPC modulates β-cleavage of APP by BACE1 protease.40 These workers have gone further to define an anti-amyloidogenic effect arising from an interaction with the protease prodomain impeding BACE maturation.41

Physiology of Ion Channels, Memory Deficits

On a cellular level, neurophysiological approaches are increasingly employed to advance our understanding of the interactions between PrP and Aβ at the level of the membrane, and upon the process of synaptic transmission in the brain. Extracellular applications of aggregated forms of both PrP and Aβ have been shown to induce acute changes in the electrophysiological properties of neuronal cells that could result in a disruption of ionic homeostasis, cell dysfunction and eventual cell death.42, 43–48 Of particular relevance to AD, both an internal (106–126) PrP peptide and soluble oligomeric Aβ1–42 modulate an identical suite of ionic conductances in cholinergic basal forebrain neurons that are an epicenter of AD pathology.45,46 Furthermore, the effects of Aβ1–42 in depressing potassium conductances in such neurons are abrogated in animals that do not express PrPC and that the PrP-Aβ interactions in neurons from wild-type mice can be blocked with a PrP antibody, Sha31.48 At a synaptic level, the initial report by Lauren et al., demonstrating that Aβ−mediated depression of hippocampal long-term potentiation is reversed in PrP null mice, has been challenged by reports from several groups that the deleterious effects of Aβ do not require PrP expression.49,50 More recently, however, Freier et al. reported that standardized Aβ-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity in a PrP-dependent manner and that Aβ obtained from ex vivo human material does the same. Furthermore, using monoclonal antibodies directed at two different PrPC epitopes, these and other authors successfully blocked the Aβ-mediated disruption of synaptic plasticity.51 With regards to memory function in intact animals, Gimbel and coworkers reported that PrP gene deletion improved impairment in the Morris water maze in a transgenic model of AD,52 a different transgenic AD line did not yield the same effects,53 and another lab could not score an effect of Prnp genotype on a behavioral task when Aβ oligomers were applied as toxic reagents.54

PrPC as a Neuroprotective Molecule Vs. Fair Game for AD Therapy

Some of the foregoing data advance anti-PrP antibodies as potential AD therapies.51,55 However this view of PrPC as a latent pro-pathogenic target molecule is in apparent contradiction with the observation that PrPC is often neuroprotective in whole animal models, and is needed to protect or maintain the adult CNS and PNS,56 perhaps by mediating stress signals.19,57 One neurotoxic paradigm of potential relevance to AD is that overexpression of human APP in mice leads to neonatal mortality, likely mediated by endoproteolytic products of APP, and these most notably including different forms of Aβ. Here there is a spread of data. While improvements in this parameter were noted in TgPS1delta E9/APPSwe mice deleted for the PrP gene,52 there was no such effect of Prnp genotype in the J20 line of TgAD mice.53 TgCRND8 mice58 are a yet different line of TgAPP mice with more profound deposition of Aβ, starting at 3 mo of age, and in our own trial studies 90% of neonatal mice lacking one copy of Prnp did not survive to 100 d of age (Fig. 2), in contrast to an earlier figures of 40–60% mortality.58 Two interpretations here are that (1) a modifier gene governing postnatal mortality has been introduced in the genetic background of the Prnp0/0 mice, or that (2) the presence of a wt Prnp gene (and presumably PrPC) protects against APP overexpression. Inevitably, the task of weighing PrPC’s contribution in AD models is entangled in the limitations of said models, which most typically lack neuronal loss, and lack florid tauopathy deriving from endogenous tau. Since these genetically engineered mice derive from familial AD, there are also assumptions that have been made in their creation. Such assumptions do not apply to wild-type mice, which may comprise a simpler benchmark for some types of studies. But, surprisingly, even here there is a debate as to the toxic or neutral effects of anti-PrP antibodies on neuronal viability,59-61 before any action in relationship to Aβ is considered.

graphic file with name prio-6-359-g2.jpg

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Figure 2. Survival Data of TgCRND8 “Alzheimer mice” with 50% PrP gene dosage. Survival curves for Prnp0/+ mice with or without the mutant human APP transgene array (APP695, KM670/671NL + V717F) present in the TgCRND8 transgenic line. Average survival time and standard deviation were 76 d ± 42 d (n = 10, median 65 d) vs. no deaths in the control group terminated as healthy at 222 or 228 d (n = 9). A minimal estimate of distinction from the Prnp0/+ control group gave a chi square value 14.47, p = 0.001 (Gehan-Breslow-Wilcoxon test).

Prevailing Questions

As can be appreciated, even after stratifying the available data by technical parameters, there is still no lack of controversy in the union of PrPC and Aβ. While some disputes might be ascribed to imperfections and variance in current AD models, others cannot; for example the theory of pro-pathogenic effect of PrPC mediating Aβ inhibition of synaptic activity opposes anti-pathogenic action by inhibition of BACE, and may oppose anti-pathogenic neuroprotective activity seen in animal models. For this pioneering area to show a significant advance, technologies will be needed to isolate – by genetic or biophysical means – the different bioactive forms of PrPC and Aβ. In conjunction with the most sophisticated models of AD to capture crucial biological endpoints, the situation may become clearer as to whether PrP is a crucial waystation in AD pathogenesis or a temporary detour from a surer path.

Acknowledgments

This research was supported by a grant from the Alberta Prion Research Institute, the Alberta Ingenuity Fund, the PrioNet Network Centre of Excellence and the Canadian Institutes of Health Research. We thank David MacTavish, Jing Yang and Beipei Shi for technical assistance

Note Added in Proof

Strittmatter and co-workers have recently described the ability of PrPC to mediate the toxic action of Aβ oligomers by the activation of Fyn kinase (Um et al. Nat Neurosci 2012; In press; PMID 22820466).

Footnotes

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