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Complement Proteins May Provide a Gateway to Early Alzheimer’s Disease Therapeutics

Complement Proteins May Provide a Gateway to Early Alzheimer’s Disease Therapeutics

The classical complement pathway recognizes pathogens and uses macrophage-mediated phagocytosis to fight infection (1). In the brain, the complement pathway prunes synapses through microglia-mediated phagocytosis to fine-tune neuronal development (1). However, this process can go awry if it is activated later in life. Recently, the complement pathway has garnered a lot of attention for its connection to schizophrenia.  Specifically, a landmark study by Sekar et al showed that the very highly associated schizophrenia risk allele, complement component 4A (C4A), resulted in more C4A protein production in schizophrenic brain tissue (2). Importantly, the authors found that C4 deficiency reduces synaptic pruning in mice (2). This result provided mechanistic rationale for the pronounced synaptic loss experienced by schizophrenic patients. Moving forward, it will be very interesting to determine whether overexpression of C4 increases synaptic pruning in rodent models, as too much pruning is the expected phenotype in schizophrenia.

Beyond schizophrenia, the complement pathway was further tied to synaptic pruning in early Alzheimer’s disease (AD) through elegant work by Hong et al (3). Using super-resolution structured illumination microscopy (SIM, ~150-300nm resolution) in a mouse model of AD, the authors showed that complement component 1q (C1q) expression was increased in the dentate gyrus and frontal cortex (3). Increased C1q expression was localized to synapses and dependent on Aβ expression (3). In wildtype mice, administration of soluble oligomeric Aβ reduced synapse number via the complement pathway, as Aβ had no effect in C1q knockout mice (3). This result indicated that the complement pathway may propagate early AD pathology, as the effects of C1q on synapse loss were mediated before Aβ plaque deposition (a hallmark of late-stage AD). Perhaps the most exciting result from this study was demonstrated by biologic and genetic targeting of complement proteins. In wild type mice, administration of a C1q antibody rescued synapse loss and neuronal function (as determined by LTP) in the presence of oligomeric Aβ (3) (Figure, taken from Hong et al). Further, in an AD mouse model, genetic knockout of downstream complement component 3 (C3) rescued synapse loss (3). These results highlight the therapeutic potential of complement inhibitors for early-stage AD treatment.

Together these studies illuminate an entry point to prevent aberrant synaptic pruning. I look forward to future studies investigating the effects of complement inhibition on memory and learning behaviors in schizophrenia and AD models.


1) Stephan AH, Barres BA, and Stevens B, Annu Rev Neurosci, 2012.

2) Sekar A et al., Nature, 2016.

3)Hong S et al., Science, 2016.