. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron. 2015 Jan 7;85(1):101-15. Epub 2014 Dec 18 PubMed.


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  1. I think this is a very interesting study! It had already been long known that classical complement cascade is profoundly overactivated in Alzheimer's disease brains. The question had been whether this is driving neurodegeneration or just secondary to it. Most people seemed to have favored the latter, until Beth Stevens and I showed that complement component C1q bound to many synapses in the developing brain and that the classical complement cascade was driving synapse pruning/loss in the normal developing brain (Stevens et al., 2007). Not only did we show that the classical cascade mediated synapse pruning, we showed that the classical complement pathway became reactivated again as the earliest sign of pathology in the neurodegenerative disease glaucoma. In fact Andrea Tenner had shown that C1q deficiency was neuroprotective in mouse models of Alzheimers which had less synapse loss (Fonesca et al., 2004). So Beth and I proposed that C1q and the classical complement cascade would be a universal driver of synapse loss in many neurodegenerative diseases, including Alzheimer's. I became so enthusiastic about this that four years ago I co-founded a company, Annexon Biosciences, that has made the first therapeutic that targets C1q and blocks the classical complement cascade.

    Lian et al. have now provided further direct evidence for a role of the complement cascade component C3 in driving synapse loss in mouse models of Alzheimer's. As others, for example Tenner's group, had done before them, they showed that C3 levels are elevated (see Zhou et al., 2008). This C3 is made by reactive astrocytes. In fact, my lab showed a year or two ago that reactive astrocytes strongly upregulate all the needed classical complement cascade components to run synapse attack, including C1r, C1s, C4, C2, and C3 (Zamanian et al., 2012), with microglia and sick neurons both making C1q. All the pieces seem to be coming together.

    Overall I think the main importance of what Lian et al. have done is to show that pharmacological blockade of the complement system is therapeutic in mouse models of Alzheimer's. Because there are not yet any good drugs to block the classical complement cascade, they could only test an already-established C3aR blocking drug. The problem with this approach is that it is very indirect, because C3aR is not required for the classical complement cascade to mediate synapse loss. That requires synaptic C1q binding and then activation of the cascade leading to deposition of C3b on synapses, which are then eliminated by microglial phagocytosis, the latter being mediated by the microglial C3b receptor called CD11b. Microglia make C3aR, and in fact I doubt the authors' assertion that neurons express the receptor. Therefore, when C3 is cleaved upon complement activation, the C3a fragment does not bind to the synapse, rather it is a chemotactic factor that helps recruit microglia to eat the synapse. But because microglia are already everywhere, the synapses tagged by C3b will be eaten regardless of whether C3aR is blocked or not. Most likely this is why Lian et al. only demonstrate relatively small effects on synapse number and protection. I think the critical question now is whether direct pharmacological blockers of C1q and the classical complement cascade will be neuroprotective. 


    . The classical complement cascade mediates CNS synapse elimination. Cell. 2007 Dec 14;131(6):1164-78. PubMed.

    . Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci. 2004 Jul 21;24(29):6457-65. PubMed.

    . Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease. J Neurochem. 2008 Sep;106(5):2080-92. PubMed.

    . Genomic analysis of reactive astrogliosis. J Neurosci. 2012 May 2;32(18):6391-410. PubMed.

  2. Overall, this paper from Hui Zheng's lab is very interesting. The researchers provide further evidence for the role of C3 and complement in neuronal function and dysfunction in Alzheimer's disease as well as the complement pathway as a potential therapeutic target in AD and other neurodegenerative diseases. 

    This work also highlights a novel mechanism by which astrocytes and astrocyte-neuronal signaling contribute to neuronal and synaptic function and dysfunction. Their finding that reactive astrocytes make C3 (along with other complement components) is consistent with work from the Barres lab and others.

    Most of their paper focuses on the relationship between NFκB and C3 under basal conditions. Their hypothesis, which is a bit complicated, is that NFκB-induced astrocytic C3 activates the neuronal C3a receptor, which leads to increased intraneuronal Ca2+ signaling, which ultimately leads to alterations in neuronal structure and function. It is interesting that they see this affecting excitatory but not inhibitory synapses. This raises questions about what makes excitatory synapses vulnerable in this context.

    The authors report that C3aR antagonist treatment in plaque-deposited APP/TTA mice leads to behavioral rescue in spatial working memory. This is an important finding because they are able to rescue cognitive defects at later stages of disease progression; however, the underlying mechanisms for that rescue are not yet clear. It will be important to address whether (and how) C3aR antagonists restores neuronal and synaptic dysfunction in AD models.

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