Zhou J, Wade SD, Graykowski D, Xiao MF, Zhao B, Giannini LA, Hanson JE, van Swieten JC, Sheng M, Worley PF, Dejanovic B. The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration. Sci Transl Med. 2023 Mar 29;15(689):eadf0141. PubMed.

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  1. This is such an interesting finding. NPTX2 concentration appears over and over as clearly reduced in CSF from patients with neurodegenerative diseases but no one has known why. Perhaps this reduction reflects increased complement- and NPTX2-dependent synaptic removal by microglia across neurodegenerative diseases. This would make CSF NPTX-2 a very important biomarker in clinical trials of disease-modifying treatments in the neurodegeneration field as a whole.

    View all comments by Henrik Zetterberg

  2. This study provides an important advance to the field by highlighting a novel complement regulatory function of neuronal pentraxin 2 within the mouse CNS, and by demonstrating its relevance to pathological contexts. In addition, given the broad spectrum of neurodevelopmental and neurodegenerative diseases in which changes in the CSF levels of NPTX2 have been shown to correlate with measures of disease progression, this work provides new mechanistic insight toward understanding NPTX2 as a fluid biomarker.

    Zhou et al. show that NPTX2 can bind C1q and inhibit the classical complement cascade, using a series of in vitro binding and functional assays. In so doing, they recapitulate and expand on the findings of Kovács et al., 2021. Importantly, they demonstrate that, in the absence of NPTX2, adult mice show increased complement pathway activity, as well as elevated microglial engulfment of synaptic proteins and a reduction in the density of different synaptic populations, suggesting that NPTX2 could be eliciting similar complement inhibitory actions in the mouse CNS. Zhou et al. strengthen these findings by demonstrating that some of these phenotypes are mitigated when C1q is genetically ablated or after acute treatment with a C1Q function blocking antibody.

    They also find that that overexpressing NPTX2 in neuronal populations is sufficient to reduce microglial-mediated synapse loss and elicit protection from neuronal death in contexts where expression of complement proteins and activation of the complement pathway are elevated, thus providing evidence that manipulating levels of NPTX2 in pathological/neurodegenerative contexts is sufficient to prevent some of the microglial phenotypes and synapse loss observed in these contexts. Finally, they present compelling evidence that interaction between C1Q and NPTX2 can be observed in the human CNS and, importantly, that reductions in the levels of NPTX2-C1q complexes can be observed in the CSF of symptomatic FTD patients, which they then show correlates with predicted elevations of analytes that reflect downstream complement activation.

    The strengths of the authors’ study lie in the breadth of models, tools, and readouts they have used to characterize NPTX2’s role as a complement inhibitor and its potential to regulate complement activity within the mouse CNS in a variety of contexts. The translational relevance of the complement interactions to human disease is also highlighted by their interrogation of CSF samples from FTD patients, and the implication that a combined measure of complement and NPTX2 could refine the use of these as fluid biomarkers.

    The long-term impact and significance of their strategy to overexpress NPTX2 in the tauopathy model will be important to explore. For example, are the impairments in synaptic function, cognitive performance, and other behavioral phenotypes that have been described to exist in this model, ameliorated or returned to wild-type levels of performance? And are these effects specific to NPTX2, or related to its synaptic localization or neuronal activity-dependent secretion? It also remains to be investigated what upstream pathological mechanism might interrupt NPTX2’s complement inhibitory function, given that levels of NPTX2 itself do not appear to be dramatically reduced in the brains of tauopathy model mice. Is it possible that levels of C1q increase beyond the point at which NPTX2 can restrain its activity, or are other factors at play?

    One caveat to consider is that the phenotypes the authors describe for the NPTX2 KO may not all arise through interactions of NPTX2 with C1Q and a subsequent inhibition of the complement cascade. As the authors themselves raise in both the introduction and discussion, NPTX2 has previously been described to play an activity-dependent role in the strengthening and maturation of GluA4 AMPA-R containing excitatory synapses (Sia et al., 2007), as well as synaptogenesis and the generation of postsynaptic specializations (O’Brien et al., 1999; Lee et al., 2017). As the authors acknowledge, some synaptic phenotypes might arise from these other biological roles of NPTX2, independent of its interactions with complement.

    Future studies to interrogate this will be informative as they will help to address the question of whether, in the healthy adult CNS, the complement pathway is constantly primed and ready to mediate synaptic changes and is being restrained from doing so by the inhibitory actions of NPTX2 and other regulators, or if other factors/mechanisms are required to initiate this process. Further studies to explore what role, if any, NPTX2 plays during brain development, or whether the NPTX2 C1Q interaction shows any regional or temporal specification in the adult, will be informative.

    Given the broad spectrum of neurodevelopmental and neurodegenerative diseases in which changes in CSF levels of NPTX2 have been shown to correlate with measures of disease progression, the translational relevance of this study is particularly high, and the mechanistic insight it provides is valuable (Libiger et al., 2021; Belbin et al., 2020; van der Ende et al., 2020; Xiao et al., 2021). This is particularly true in light of other work that has highlighted changes in CSF complement protein levels in a similarly broad range of disease indications (van der Ende et al., 2022; Zelek et al., 2020; Gracias et al., 2022). It will be interesting to see whether measuring NPTX2-C1Q interactions in human CSF with the PLA assay could offer improvements over measures of C1Q and NPTX2 alone, as either predictive or prognostic biomarkers.

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    View all comments by Beth Stevens

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  1. Neuronal Pentraxin 2 Binds Complement Protein, Protects Synapses