. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017 May 31;9(392) PubMed.


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  1. The rigorous quantitative data in this paper support the rationale for investigation of a less-studied group of therapeutics—those inhibiting complement-activation-dependent processes—for treatment of AD and likely for other neurodegenerative disorders, and even aging itself. A main conclusion of this study is that C3-deficiency alters the glial response to amyloid plaques, and subsequently spares cognitive impairment. The data add to the growing awareness that amyloid is necessary but not sufficient for cognitive decline, and that “the reaction of glia to the plaques” is more critical, as is also apparent in human studies. While C3 deficiency protected against hippocampal synapse loss and cognitive flexibility, as the authors point out, either “C3 or its downstream activation fragments such as C3a, C5a and C5b-9 may play an important role in synapse loss and neurodegeneration.” Our previous work (Fonseca, et al., 2009) with a C5a receptor antagonist (i.e., pharmacologic inhibition of a downstream event resulting from complement activation) in two models of AD had an impact on cognitive decline. This current study supports the continuation of targeted investigations of interventions that either work alone, additively, or synergistically with other treatments to prevent cognitive loss. The recent paper from Liddelow and Barres and colleagues showing an upregulation of C3 as a marker for A1 astrocytes in response to one inflammatory signal, LPS, suggests the value of further investigations into whether the induced astrocyte C3 itself via its activation fragments and/or downstream effectors is contributing to the neurotoxicity in these models (Liddelow et al., 2017).

    Also notable is the localized/precise quantification of pathology presented in this paper, which highlights the importance of localized changes in the analysis of these models of neurodegeneration (ex. Figure 6, neuron number in CA3 and CA1, and synaptic proteins in hippocampal synaptosomes in Figure 5D). The lack of such extensive analysis in previous studies may contribute to perceived discrepancies between other reports. Kinetic studies correlating pathology, gene expression, neuronal integrity, and behavior will be useful in comparing models and arriving at causative events of dysfunction. This will certainly be a consideration in designing precision human therapeutics, as unnecessarily eliminating the beneficial functions of the complement system in responding to infection and clearance of apoptotic cells and cellular debris should be avoided if possible.

    Finally, the authors nicely discuss the limitations of this study, and others, demonstrating the need for future investigations with animal models lacking overexpression of amyloid and presenilin proteins, which will more closely mimic the human sporadic AD condition, as well as the use of inducible and/or conditional KO mice. This very nice paper should be of high impact for the field.


    . Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J Immunol. 2009 Jul 15;183(2):1375-83. Epub 2009 Jun 26 PubMed.

    . Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan 26;541(7638):481-487. Epub 2017 Jan 18 PubMed.

    View all comments by Andrea Tenner
  2. This paper follows a series of studies by Lemere and colleagues related to the role of complement factor 3 (C3), a central molecule in the complement cascade, in brain aging and Alzheimer’s disease (AD). In particular, the group recently showed that C3 deficiency affords a general protection against age-associated memory decline (Shi et al., 2015). The current report demonstrates a beneficial effect of C3 ablation in rescuing the learning and memory impairment and region-specific neuronal and synapse loss in aged APP/PS1 mice and implicates elevated BDNF/CREB signaling as a potential mechanism. Interestingly, the authors revealed that C3 deficiency results in improved cognitive performance but worsened Aβ pathology. Although the reason for such a contrasting effect and its apparent age-, region-, and possibly strain-dependency is unclear, the data indicates that Aβ load and neuronal and synaptic function can be uncoupled. The protective effect of C3 inactivation is in agreement with our data that aberrant C3 activation, through its cleavage product C3a and interaction with the C3aR, impinges on neuron-glia interaction relevant to AD (Lian et al., 2015; Lian et al., 2016). Overall these findings demonstrate an important role of C3-mediated neuron-immune system cross-talk in AD and support the notion that antagonizing this pathway may be therapeutically beneficial.


    . Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline. J Neurosci. 2015 Sep 23;35(38):13029-42. PubMed.

    . 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.

    . Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease. J Neurosci. 2016 Jan 13;36(2):577-89. PubMed.

    View all comments by Hui Zheng
  3. The protein-complement cascade is a major innate immune response mechanism. In this elegant report, Cindy Lemere’s group focused on complement component 3 (C3), which is at the epicenter of the complement cascade and a critical building block for the membrane attack complex (MAC). The authors have dissected a complex network of regulatory factors and have shown that C3 is a multifunctional protein that plays key roles in opsonization of synapses and Aβ, immune modulation, and MAC formation. What’s more, this study shows that the protein complement pathway plays a dominant role in synaptic decline in AD; distinct from changes that occur in normal aging. With respect to the amyloid cascade hypothesis, Aβ-dependent synaptic loss seems entirely complement-driven, once C3 is activated. There is translational value here, too—inhibiting C3 function is a novel therapeutic target to prevent synaptic loss in late onset AD. At the mechanistic level, preventing C3 from activating the MAC would be expected to spare AD-related synaptic loss.

    View all comments by Terrence Town

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