. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci. 2012 Sep;15(9):1227-35. Epub 2012 Jul 22 PubMed.


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  1. Of all Src kinases, Fyn is assuming a critical role in mediating Aβ toxicity. In this Nature Neuroscience paper, Stephen Strittmatter and colleagues show that oligomeric forms of Aβ bind to PrPC, a protein on the extracellular side of the membrane, and thereby activate (by an as-yet unknown mechanism) Fyn, which is localized on the intracellular side. The findings do not rule out that Aβ also binds to other receptors and/or the lipid membrane in exerting, in part, its toxic effects.

    This study by Um et al. is very carefully done, employing APP transgenic and PrP knockout mice and several cellular systems. We previously showed that tau is critical in targeting Fyn to the dendritic spine, thereby mediating Aβ toxicity (Ittner et al., 2010). In our study we did not investigate how Aβ might interact with cell surface receptors and/or the plasma membrane. Um et al. identify PrP as the protein with which Aβ interacts to cause Fyn activation. They showed further that in human AD brain, the Aβ species interacting with PrPC is present at critical levels. They further analyzed NMDAR activation upon exposure to Aβ and found phosphorylation at T1472 that was absent on a Fyn knockout background.

    When the authors crossed APP/PSEN mutant mice onto a Prnp-null background, they found that this prevented spontaneous seizures (recorded with EEG) and fully extended lifespan. These data are very similar to what we (Ittner et al., 2010) and the Mucke lab (Roberson et al., 2007) reported for the susceptibility to pentylenetetrazol-induced seizures and lifespan when crossing our APP mutant strains onto a MAPT knockout background. or with mice expressing a truncated form of tau. Also, the survival curve of the APP/PSEN mice (Um et al.) is very similar to that of the J20 and the APP23 mice (Ittner/Roberson), pointing to shared pathomechanisms in the investigated mouse strains.

    One of the most interesting aspects of the current study, as also pointed out by the authors, is that toxicity occurs during a short time window, after which the Fyn counterplayer STEP is activated. In our study, we found that disrupting the NMDAR complex with a small peptide for eight weeks protected APP23 mice permanently from seizure susceptibility, memory impairment, and reduced lifespan, indicating that there are mechanisms in place (possibly by restructuring the NMDAR) that protect the mice from Aβ’s toxicity even after the small peptide is removed. It will be interesting to further examine the Aβ-PrPC-Fyn-tau pathway, and to understand better the modes of acute and chronic Aβ toxicity.


    . Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.

    . Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.

  2. This paper by the Strittmatter group describes a significant number of data; however, the relevance of these results remains unclear. All the in-vitro data are produced with short exposure to oligomers (15-20 minutes, sometimes hours). We do not know how long the mechanism remains. When the observation is prolonged in primary cultures to test toxicity, a negligible effect was found at two hours (10 percent of LDH increase and no changes in MTT; Fig. S8 and 5h and 5i) and no effect at 72 hours (S9). Also, the measure of spines gave a modest effect after five hours of exposure to oligomers (Fig. 6b). In addition, the mechanism responsible for the relationship between Aβo/PrP/Fyn and NMDA receptors is elusive.

    While the number of experiments with different conditions and the continuous referral to supplemental information does not help the reader, this is an interesting scientific issue.

    In-vivo experiments show that the epileptic status of the APPSwe/PSenΔE9 mice was strongly attenuated when PrPC was nullified. This result may indicate a potential interaction between the expressed transgene and PrPC, but epileptic discharge is strictly associated with this specific transgenic mouse. Other APP single, double, and triple Tg mice, as well as most AD subjects, do not show this condition. In our lab we have conducted a specific investigation into this aspect, comparing three different Tg mice (PDAPP, TASTPM, and APP/PS2/TAU) in the framework of EC-IMI-Pharmacog project, with at least one week of continuous EEG recordings. We have not seen evidence of epilepsy in any animals.

    In conclusion, the results presented in this paper confirmed the high-affinity association between Aβo and PrPC. Downstream, and in the specific conditions used, Fyn signaling might be activated. However, as mentioned by the authors in the text, and in contrast with the picture of Fig. S10, the physical interaction of PrPC with Fyn is unlikely since PrPC is attached extracellularly to the membrane with a GPI anchor, while Fyn is inside the cell. Furthermore, the timing and the quantitative effects associated with the Aβo/PrPC/Fyn mechanism, in terms of synaptic dysfunction, interaction with NMDA receptors, and toxicity, leave doubts as to the relevance of the phenomenon.

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