Abstract
Elements of the immune system particularly that of innate immunity, play important roles beyond their traditional tasks in host defense, including manifold roles in the nervous system. Complement-mediated synaptic pruning is essential in the developing and healthy functioning brain and becomes aberrant in neurodegenerative disorders. C1q, component of the classical complement pathway, plays a central role in tagging synapses for elimination; however, the underlying molecular mechanisms and interaction partners are mostly unknown. Neuronal pentraxins (NPs) are involved in synapse formation and plasticity, moreover, NP1 contributes to cell death and neurodegeneration under adverse conditions. Here, we investigated the potential interaction between C1q and NPs, and its role in microglial phagocytosis of synapses in adult mice. We verified in vitro that NPs interact with C1q, as well as activate the complement system. Flow cytometry, immunostaining and co-immunoprecipitation showed that synapse-bound C1q colocalizes and interacts with NPs. High-resolution confocal microscopy revealed that microglia-surrounded C1q-tagged synapses are NP1 positive. We have also observed the synaptic occurrence of C4 suggesting that activation of the classical pathway cannot be ruled out in synaptic plasticity in healthy adult animals. In summary, our results indicate that NPs play a regulatory role in the synaptic function of C1q. Whether this role can be intensified upon pathological conditions, such as in Alzheimer’s disease, is to be disclosed.
Highlights
Complement components and pentraxins represent major humoral factors of the innate immune system, that often in collaboration play important roles in host defense, removal of dead cells, and several other physiological processes [1,2,3,4]
We addressed whether Neuronal pentraxins (NPs) could bind to the entire C1 complex consisting of C1q and serine proteases C1r and C1s
We further investigated if the demonstrated interactions are functional and strong enough to trigger activation of the classical pathway of the complement system
Summary
Complement components and pentraxins represent major humoral factors of the innate immune system, that often in collaboration play important roles in host defense, removal of dead cells, and several other physiological processes [1,2,3,4]. Maladaptive synaptic connectivity is usually a core component in the pathology of central nervous system (CNS) diseases, such as autism spectrum disorders [5] and schizophrenia [6]. Secreted microglial complement components C1q and C3b are deposited onto synapses to be eliminated leading to their recognition and engulfment by surrounding microglia [10, 11] in a yet not fully understood manner. Disturbances in complement-dependent synaptic pruning are in a causal relationship with the development of neurodegenerative disorders, schizophrenia, and epilepsy [5,6,7,8, 12], and recently reviewed by Tenner et al [13], pointing out that properly functioning complement-mediated synapse elimination is indispensable for normal CNS functions. The average lifetime of synapses show large variety [15,16,17]; synapses are constantly renewed, and it is relevant to carry out studies on adult mice
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