. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300. PubMed.


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  1. This is an interesting study that addresses two important issues relating to the role of Aβ in memory impairment, namely biophysical characterization of synthetic memory-impairing assemblies and the requirement of PrPc for memory impairment. Using atomic force microscopy (AFM) and size exclusion chromatography (SEC), Balducci and colleagues characterized four distinct Aβ1-42 preparations. Freshly dissolved unaggregated Aβ, seemingly mostly Aβ monomer; Aβ fibrils formed at low pH; and Aβ were incubated at either 4oC or 22oC for 24 hours and contained different heterogeneous mixtures of Aβ monomer and small prefibrillar Aβ assemblies. The latter mixtures are simply referred to as “oligomers.”

    Each preparation was then tested for its effect using the novel object recognition task. The initial paradigm involved intracerebroventricular injections (icv) of vehicle or one of the Aβ preparations. Injections were made at two hours prior to mice being allowed to explore two identical objects and then again two hours before animals were tested for 24 hours’ recall by exposure to two objects: one familiar and one novel. Animals injected with Aβ monomer or Aβ fibrils behaved in a manner highly similar to those injected with vehicle, whereas mice injected with either the 4oC or the 22oC “oligomers” were unable to discriminate between the novel and the familiar object.

    Importantly, this effect required only tiny amounts of Aβ. For instance, injection of only 30 ng x 2 of the “oligomer” preps was sufficient to impair object recognition. But given that monomer was the most abundant component of the 4oC “oligomer” prep, it seems highly likely that the amount of active Aβ species was much lower, probably in the order of 0.15 to 0.75 ng x 2. Compared to prior studies testing the effect of non-fibrillar Aβ assemblies on memory, the concentrations used by Balducci and colleagues are comparable to those used to demonstrate impairment of ALCR performance by icv injection of ADDLs (Reed et al., 2009), but are substantially lower than the concentration of lipid-induced reverse protofibrils used to induce impairment of avoidance learning and contextual fear conditioning (Martins et al., 2008). Thus, a highlight of the current study is the fact that the relatively simple and fast object recognition task is sensitive to very low concentrations of certain Aβ assembly forms.

    Interestingly, when animals were allowed to recover and tested for recall nine days after the second Aβ injection, the impairment of object recognition did not persist. This finding suggests that animals injected two hours prior to familiarization were able to encode the memory of the familiar object, but that “oligomer” injection two hours prior to 24-hour recall prevented retrieval, whereas the same injection was not able to prevent retrieval at 10 days. However, these data appear to be in conflict with the finding that a single injection of “oligomers” at two hours prior to familiarization impaired recall at 24 hours, whereas injection of “oligomers” at two hours prior to recall had no effect. Thus, further work is required to discern how injection of “oligomers” prior to familiarization, which seemly perturbs encoding, could be overcome by simply testing after a longer duration. Nonetheless, Balducci et al. have clearly demonstrated the utility of this paradigm.

    They next turned their attention to determine whether or not the observed “oligomer”-mediated impairment required PrPc. This they addressed using PrP knockout (KO) mice. Prior work by Lauren et al. (2009) using murine hippocampal slices bathed in medium containing ADDLs (Lambert et al., 1998) demonstrated that PrPc was required for the Aβ-mediated block of LTP; thus, one might have anticipated that Balducci and colleagues would find PrP KO animals resistant to the memory-impairing effects of their “oligomer” prep. However, this was not the case. When PrP KO mice were injected with either 4oC or 22oC “oligomers,” these animals could not discriminate between the familiar and the novel object. Although not required for Aβ-mediated impairment of object recognition, Balducci et al. reported that their “oligomer” preps bound to brain-derived PrPc.

    Why PrPc binds certain forms of Aβ and appears to be required for Aβ-mediated impairment of LTP (an observation we have replicated in my lab), but not the impairment of object recognition, is unclear. Experimental differences including differences in the actual Aβ species used, their effective concentration, and the genetic background of the PrP KO animals could contribute to these divergent results. Whatever the reason, using PrP KO mice, it will be important to simultaneously test the effect of well-defined Aβ assemblies on both LTP and hippocampal-dependent behavioral paradigms known to parallel LTP (e.g., avoidance learning, Whitlock et al., 2006). Regardless of the outcome of future studies, it is already clear that the link between Aβ, PrP, and Alzheimer disease is not as simple as it first appeared.


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    . Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233):1128-32. PubMed.

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    . Learning induces long-term potentiation in the hippocampus. Science. 2006 Aug 25;313(5790):1093-7. PubMed.

  2. This study further explores interaction between Aβ oligomers and cellular prion protein (PrPC) as proposed by Laurén et al., 2009. In the current study, the authors incubated Aβ1-42 to generate oligomers, which were assayed for the ability to bind PrPC and to affect recognition memory. While this synthetic Aβ preparation did bind endogenous PrPC in a dose-dependent fashion, the effect of Aβ oligomers on recognition memory was not significantly different between wild-type and PrPC knockout mice. This convincing study by Balducci et al. has a number of controls, such as comparing the effects of fibrils and rescuing the effects on memory with an anti-Aβ antibody.

    The critical question that remains, though, is how to reconcile these findings with those by Laurén et al. One key point is that the physiologic assay used in these studies is different—long-term potentiation by theta burst stimulation in Laurén et al. and recognition memory and toxicity in Balducci et al. The former is an in vitro electrophysiologic phenomenon studied in a well-characterized and simplified acute hippocampal slice preparation. It is unclear how LTP in hippocampus precisely correlates with recognition memory, which is tested in the context of completely intact neural circuitry. Given the complexities in the vast literature describing Aβ interactions with neuronal receptors, it remains highly plausible that the various pathophysiologic effects of this hydrophobic peptide are driven by a number of receptor pathways. Consequently, this study affirms that dissecting mechanisms of AD pathology is made even more difficult by our incomplete understanding of the requirements for normal neural physiology.


    . Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233):1128-32. PubMed.