Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ. Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science. 2013 Sep 20;341(6152):1399-404. PubMed.
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Gladstone Institutes/UCSF
Aβ oligomers bind to multiple proteins and have diverse effects in cell culture and animal models of the disease, depending on a plethora of variables such as oligomer species, length of exposure of neurons to oligomers, mutations harbored by transgenic mice, type of transgenes, etc... Mechanisms by which Aβ oligomers cause neuronal network dysfunction have been sparse in the literature, and many groups in the field of AD research focus on trying to understand these mechanisms. The study by Kim & al. identifies PirB and its human ortholog LilrB2 as receptors for Aβ oligomers. Thus, this study expands the list of proteins that have been identified as key mediators of Aβ oligomer-dependent toxicity. The authors used a wide range of approaches, including biochemical assays, electrophysiology and behavior that were well designed to provide convincing clues and new leads on how these toxic species impair cognitive functions and elicit memory impairments in an AD model.
The authors identify the two most N-terminal Ig domains of PirB and LilrB2 as critical for interaction with high-n Aβ oligomers as deletion of these domains significantly abrogates this interaction. It is interesting to note that low-n oligomers (dimers and trimers) were not pulled down with PirB-Fc or LilrB2-Fc. This raises the possibility of a receptor selectivity based on Aβ oligomers species. However, the authors did not clearly identify the specific oligomeric Aβ involved in this interaction. In this study for instance, could Aβ*56 be the main oligomer species causing the neuronal network dysfunction in the APP/PS1 line? Another important point is that the authors did not test other sources of Aβ oligomers (i.e. CHO-derived or AD brain-extracted Aβ oligomers) that have been shown to be more potent than synthetic and might be less prone to artificial interaction.
The authors also show that Aβ oligomer binding to neuronal cells was not fully abolished in the absence of PirB, meaning that additional receptors exist. This is not surprising in light of the literature and the growing number of proteins that have been shown to bind Aβ oligomers. Aβ oligomers affect many signaling pathways to cause spine loss and cognitive deficits, it is therefore tempting to speculate that normalizing/fixing only one of these different pathways might be sufficient to alleviate or prevent these deficits.
The authors also established that the PirB/oligomer interaction exacerbates cofilin signaling leading to dendritic spine loss and cognitive impairment. It would be very informative to examine A oligomer-induced dendritic spine loss by cell imaging and determine whether this is prevented by PirB removal in PirB-/tg mice or in cell culture.
It would also be very interesting in future studies to assess whether the PirB/oligomer interaction is present in other AD models and leads to impairment of cofilin signaling and subsequent spine loss. Although the authors assessed the rescue of cognitive deficits by two different tests (NOR and NPR), testing PirB-/tg mice in the Morris Water Maze in a follow-up study would also provide additional information.
Overall, this is a great study that contributes to a better understanding of the mechanisms by which Aβ oligomers harm the brain and opens up new leads in AD research.
View all comments by Moustapha CisseCognition Therapeutics Inc.
This is a very important manuscript demonstrating that Aβ oligomers bind to and adversely affect a molecule critical for normal learning and memory, adding to the evidence that Alzheimer’s begins and persists as a synaptic plasticity disease. It was discovered through an unbiased screen, and is another example of how this approach is proving fruitful for identifying molecular mechanisms involved in the disease process. The identification of a role for PirB as an oligomer receptor is a breakthrough for the field, and provides further support for efforts to discover and develop therapeutics that antagonize these early binding and signaling events. It holds the promise of being able to intervene in the Alzheimer's disease process, even after diagnosis, by directly blocking the effects of soluble Aβ oligomers on synapse function.
The accompanying preface to the article points out that the exact structure of Aβ oligomers that cause toxicity is still unknown, and many labs work with unstandardized heterogenous mixtures of different oligomer structures. It suggests that these unstandardized mixtures may be one reason behind the identification of several putative oligomer receptors. While it is certainly urgent that action be taken towards structural understanding of disease-relevant oligomers, an alternative interpretation is possible. Rather than exist as separate entities as is depicted in the accompanying diagram, several of these candidate receptor molecules may be closely linked in a multi-protein receptor complex, whose specific members may change as a result of electrophysiological activity or damage. Additionally, such multi-protein receptor complexes need not be exclusively postsynaptic. Indeed, molecules on both sides of the synapse are in direct contact, and this is critically required for normal function. This paper has identified a key presynaptic player in this emerging story.
The interactions that cause Alzheimer’s disease may prove to be more tractable than complex oligomer ligands and multiple receptors would currently lead us to believe. Pathological processes that behave according to pharmacological principles contain signaling nodes that are possible to target with therapeutics. It is now quite urgent to confirm that this is the case in Alzheimer’s disease. For the sake of patients and their families, let us hope so.
View all comments by Susan CatalanoMake a Comment
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