The role of complement in synaptic degeneration

Abstract

Synapse loss is an early event of many neurodegenerative diseases including Alzheimer?s disease and Parkinson?s disease. The causes and mechanisms that underpin synapse dysfunction and degeneration are poorly understood. Animal models that mimic the major disease pathologies can be used to investigate possible pathways involved. This work describes the use of two models based on the prion disease and genetic deletion of CSP? both of which are characterised by synaptic degeneration.
The ME7 model of prion disease is characterised by accumulation of misfolded prion protein, microglia activation and astrocytosis at 8 weeks post disease initiation (p.i), synaptic degeneration in the CA1 of the hippocampus at 13 weeks p.i, and neuronal loss at 16 weeks p.i. Complement proteins have been shown to be upregulated in brains of patients with a neurodegenerative disease. It has been suggested that C1q is involved in synaptic degeneration by „tagging? synapses for selective removal. qRT-PCR of 18 week p.i. hippocampus from ME7-animals reveals a >5 fold induction of C1q mRNA. This was confirmed by quantitative western blotting of 18 week hippocampus showing a disease-associated increase in C1q protein. Although C1q is induced, the time course and spatial expression do not coincide with the initiation of synapse loss in the CA1. The induction is restricted to the later stages of the disease suggesting that C1q and complement does not direct synapse loss but may contribute to the removal of the cellular debris associated with neuronal loss and/or the accumulation of misfolded prion protein.
In the second model, Cysteine String Protein ? (CSP?) knockout mice were investigated at time points beyond the P15, when they show synapse loss, but before they show premature death at P40. This model allows investigation of synaptic degeneration in the absence of accumulated misfolded protein. We investigated this in the context of the hippocampus but failed to show synapse loss at the time points investigated. In contrast we identified a robust astrogliosis consistent with an emerging neuronal dysfunction. This is likely related to the loss of parvalbumin-positive interneurones, and synapses, previously shown to be lost at this time point. This astrocytic response, in contrast to the ME7 model, occurs without the associated induction of C1q and other markers of the neuro-immune response.
Together the data show that C1q is not selectively „tagging? synapses as previously suggested, and does not contribute to the progression of prion disease. It is more likely that C1q is upregulated in the late stages of disease to aid in the clearance of cellular debris.

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ORCID for Vincent O'Connor: orcid.org/0000-0003-3185-5709

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