Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Journal Club

Is PrPC a Mediator of Aβ Toxicity in Alzheimer's Disease?

Diego Peretti
Journal of Neuroscience 8 September 2010, 30 (36) 11883-11884; DOI: https://doi.org/10.1523/JNEUROSCI.3235-10.2010
Diego Peretti
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

The amyloid hypothesis proposes that the abnormal accumulation of amyloid β peptide (Aβ) in the brain is a direct cause of neurodegeneration and cognitive decline in Alzheimer's disease (AD). This hypothesis is supported by the occurrence of pathogenic mutations in amyloid precursor protein (APP) and presenilin proteins in autosomal-dominant AD that increase Aβ generation, especially the toxic Aβ42 form (for review, see Hardy and Selkoe, 2002). More recently, soluble Aβ oligomeric species have been linked to synaptic dysfunction and learning and memory deficits, including long-term potentiation (LTP), in vitro and in vivo (for review, see Haass and Selkoe, 2007). Indeed, synaptic loss is an early event and the major structural correlate of cognitive impairment in patients with AD. Hence, major efforts have been directed to elucidate the pathways involved in Aβ toxicity.

Recently, an expression cloning screen for proteins that interact with Aβ oligomers identified the cellular prion protein, PrPC, as binding synthetic Aβ oligomers with high affinity in vitro. Further, this interaction was necessary for the inhibitory effects of Aβ oligomers on LTP in vitro (Laurén et al., 2009). Thus, in the absence of PrPC, Aβ oligomers did not impair LTP, suggesting a role for PrPC in mediating memory impairment in AD. PrPC is an interesting candidate. It is a highly conserved protein, with high levels of expression in neurons, but of unclear function. PrP-null mice are essentially phenotypically normal, but misfolded PrPC is central to the pathogenesis of prion disorders, which are also neurodegenerative diseases. If PrPC is a major player in memory impairment in AD, it could become a therapeutic target.

The role of the PrPC–Aβ interaction in vivo is the subject of a recent paper in The Journal of Neuroscience. Gimbel and colleagues (2010) address the role of PrPC in mediating the effects of brain-derived Aβ oligomers on memory in vivo, using a mouse model of AD. They tested the toxicity of Aβ oligomers in the presence and absence of PrPC in APP/PSen mice, which express two AD causal mutations, the Swedish mutation in APP and an exon-9-deleted variant of presenilin 1. APP/PSen mice have both elevated steady-state levels of Aβ42, which directly correlates to the rate of amyloid deposition, and age-dependent episodic-memory deficits without concurrent LTP impairment (Jankowsky et al., 2004; Volianskis et al., 2010). The mice also have some neuropathological changes, including degeneration of forebrain monoaminergic neurons (Liu et al., 2008) and a marked incidence of unexplained sudden death (Halford and Russell, 2009). The authors addressed the role of PrPC in these processes by crossing the APP/PSen mice to homozygous PrP-null mice of matched genetic background, thus generating APP/PSen mice with and without PrPC expression.

First, the authors analyzed whether PrPC affected the levels of APP and its products. They found no major differences with or without PrPC. These results are in contrast to reported negative regulation of β-secretase (which cleaves APP to form Aβ) by PrPC, which resulted in increased Aβ levels in PrP-null mice (Parkin et al., 2007). But APP/PSen mice express two- to fourfold more APP than wild-type mice, so this might obscure any effect of PrPC on β-secretase regulation (Jankowsky et al., 2004). What it is not clear, however, is whether APP/PSen/PrP-null crosses in this paper produce a progeny indeed devoid of all PrPC. The authors presented no data showing absence of PrPC in APP/PSen+/PrP− mice (PrP-deficient APP/PSen mice). This appears to be a critical omission. Nonetheless, even if the animals are in fact hemizygous for wild-type PrPC, the reduced PrPC levels may still give relevant functional readout for Aβ toxicity.

Next, the authors analyzed degeneration of the forebrain monoaminergic neuron afferents, an early symptom of AD that occurs in this mouse model. They found that reduced length of serotonin fibers was rescued in PrP-deficient APP/PSen mice compared with APP/PSen controls at 12 months. There were also slight but significant increases in the presynaptic and postsynaptic markers synaptophysin and PSD-95 in PrP-deficient APP/PSen mice compared with APP/PSen controls. Thus, PrPC deficiency appears to be neuroprotective in this model.

Another parameter analyzed was survival during the first year of age. APP/PSen mice showed a 60% survival rate at 12 months. This result is consistent with previous findings in the same model (Halford and Russell, 2009). The reason for this is not understood, but it also occurs with other APP mutations in transgenic mice and it is highly dependent on genetic background (Carlson et al., 1997). The phenotype was dramatically reduced in PrP-deficient APP/PSen mice, which had a survival rate of >96% at one year. This rescue is so striking that it is surprising the authors did not explore it further. It would have been interesting to analyze whether the effect on survival depends on the level of PrPC.

Next, the authors examined spatial learning and memory using the Morris water maze test. Here, mice rely on distant visual cues to navigate from a start location at the perimeter of an open swimming arena to reach a submerged (hidden) escape platform. After a set of trials, the platform location was reversed for a second set of trials, a procedure called reversal learning. The test was performed at 3 and 12 months of age. No differences were observed in control conditions of cued learning across all groups of mice. A deficit was detected in APP/PSen animals at 12 months at the end of the spatial learning (trials 5 and 6) and in reversal learning. Loss of reversal learning suggests that the animals cannot efficiently extinguish their initial learning and acquire a path to the new goal position. The deficits observed were rescued in PrP-deficient APP/PSen mice. In addition, memory was tested in the absence of a hidden platform 2 d after the last learning trial and the 12-month-old APP/PSen mice showed no preference for the location of previously learned hidden platform. The preference was rescued in PrP-deficient APP/PSen mice. PrPC deficiency also rescued the latency of APP/PSen mice to enter a dark compartment in which an aversive stimulus was delivered during a training session in the passive avoidance paradigm, based on associative emotional learning.

This work therefore appears to show a significant rescue of learning/memory deficits in APP/PSen mice in the absence of PrPC, as well as subtle neuropathological rescue and striking effects on survival. Interestingly, putting Aβ oligomers into wild-type and PrP-null mice produced an apparent impairment of memory independent of PrPC (Balducci et al., 2010). The age of the mice and the tests used here were different, but any interaction of Aβ and PrPC might be more complex than suggested.

Thus, the central hypothesis proposed by Gimbel et al. (2010) is that Aβ toxicity, not just in memory but also in sudden death and neuropathology, is mediated through PrPC. The APP and PS1 mutations in the mice used here are both under the control of prion promoter. This generates an experimental condition of Aβ production, which perfectly matches with endogenous PrPC expression. Thus, the role of PrPC as a downstream effector in the Aβ-dependent pathological cascade might be overestimated. Testing other AD transgenic mouse models in which mutations are expressed under the control of promoters not related to PrPC would be important to exclude this possibility. Further, PrPC knock-out would be predicted to rescue the phenotypes in all AD (Aβ-based) transgenic models, if indeed Aβ acts via PrPC as the authors propose. A systematic analysis of several of the other mouse models would be needed before PrPC blockade could be supported as a therapy in AD, as the authors suggest. Another approach would be to test whether expressing mutant PrPC that lacks the Aβ binding site prevents Aβ toxicity.

In conclusion, the authors showed a role for PrPC in Aβ-mediated memory impairment in this specific model. However, further studies will be required to understand the precise role of PrPC in a more realistic in vivo scenario of multiple target mediators of Aβ oligomers toxicity. Another interesting course to explore would be the understanding of common pathways among neurodegenerative disorders. Future work should screen for common downstream pathways activated. An important, unanswered question in prion disease is the identification of PrPC intermediate toxic elements and the pathways activated by them. Do the events induced by Aβ through PrPC depend on generation of a toxic PrP element? Are the pathways activated by Aβ oligomers through PrPC binding similar to those induced by PrPC binding to infectious isoform PrPSc? In a broader view, these findings and others open a window for searching for common underlying processes required for synaptic function that might be at the core of many neurodegenerative diseases with a synaptic dysfunction component.

Footnotes

  • Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.

  • I thank members of the laboratory for their insightful discussions and comments.

  • Correspondence should be addressed to Diego Peretti, Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, United Kingdom. dap22{at}le.ac.uk

References

  1. ↵
    1. Balducci C,
    2. Beeg M,
    3. Stravalaci M,
    4. Bastone A,
    5. Sclip A,
    6. Biasini E,
    7. Tapella L,
    8. Colombo L,
    9. Manzoni C,
    10. Borsello T,
    11. Chiesa R,
    12. Gobbi M,
    13. Salmona M,
    14. Forloni G
    (2010) Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A 107:2295–2300.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Carlson GA,
    2. Borchelt DR,
    3. Dake A,
    4. Turner S,
    5. Danielson V,
    6. Coffin JD,
    7. Eckman C,
    8. Meiners J,
    9. Nilsen SP,
    10. Younkin SG,
    11. Hsiao KK
    (1997) Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum Mol Genet 6:1951–1959.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Gimbel DA,
    2. Nygaard HB,
    3. Coffey EE,
    4. Gunther EC,
    5. Laurén J,
    6. Gimbel ZA,
    7. Strittmatter SM
    (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30:6367–6374.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Haass C,
    2. Selkoe DJ
    (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Halford RW,
    2. Russell DW
    (2009) Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan. Proc Natl Acad Sci U S A 106:3502–3506.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Hardy J,
    2. Selkoe DJ
    (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–356.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Jankowsky JL,
    2. Fadale DJ,
    3. Anderson J,
    4. Xu GM,
    5. Gonzales V,
    6. Jenkins NA,
    7. Copeland NG,
    8. Lee MK,
    9. Younkin LH,
    10. Wagner SL,
    11. Younkin SG,
    12. Borchelt DR
    (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Laurén J,
    2. Gimbel DA,
    3. Nygaard HB,
    4. Gilbert JW,
    5. Strittmatter SM
    (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Liu Y,
    2. Yoo MJ,
    3. Savonenko A,
    4. Stirling W,
    5. Price DL,
    6. Borchelt DR,
    7. Mamounas L,
    8. Lyons WE,
    9. Blue ME,
    10. Lee MK
    (2008) Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease. J Neurosci 28:13805–13814.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Parkin ET,
    2. Watt NT,
    3. Hussain I,
    4. Eckman EA,
    5. Eckman CB,
    6. Manson JC,
    7. Baybutt HN,
    8. Turner AJ,
    9. Hooper NM
    (2007) Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A 104:11062–11067.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Volianskis A,
    2. Køstner R,
    3. Mølgaard M,
    4. Hass S,
    5. Jensen MS
    (2010) Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1DeltaE9-deleted transgenic mice model of beta-amyloidosis. Neurobiol Aging 31:1173–1187.
    OpenUrlCrossRefPubMed
Back to top

In this issue

The Journal of Neuroscience: 30 (36)
Journal of Neuroscience
Vol. 30, Issue 36
8 Sep 2010
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Is PrPC a Mediator of Aβ Toxicity in Alzheimer's Disease?
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
Is PrPC a Mediator of Aβ Toxicity in Alzheimer's Disease?
Diego Peretti
Journal of Neuroscience 8 September 2010, 30 (36) 11883-11884; DOI: 10.1523/JNEUROSCI.3235-10.2010

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
Is PrPC a Mediator of Aβ Toxicity in Alzheimer's Disease?
Diego Peretti
Journal of Neuroscience 8 September 2010, 30 (36) 11883-11884; DOI: 10.1523/JNEUROSCI.3235-10.2010
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

  • Role of Ubiquilin-2 in Proteostasis and Tau Aggregation in Tauopathies
  • Separating Uncertainty from Surprise in Auditory Processing with Neurocomputational Models: Implications for Music Perception
  • Parabrachial Projections to PAG-RVM Axis May Promote Placebo Hypoalgesia and Nocebo Hyperalgesia
Show more Journal Club
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
(JNeurosci logo)
(SfN logo)

Copyright © 2022 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.