The synaptic connections between neurons are in a constant state of flux between birth and adulthood. As new synapses are built, a complementary biological system fine-tunes the brain by erasing other connections. The process, known as synaptic pruning, is crucial to brain development and involves a part of our immune system called the classical complement pathway; there is even evidence that defects in pruning may be involved in neurodevelopmental disorders such as schizophrenia and autism. Now, studies find that the same synaptic pruning systems present in early neurodevelopment reactivate later on in neurodegenerative diseases, such as Alzheimer’s. The findings may offer a long-sought mechanism for synapse loss in these diseases, and open the door to a potential new therapeutic approach to combat certain types of neurodegeneration.
In November 2018, a team led by Morgan Sheng*, vice president, neuroscience and Borislav Dejanovic**, a neuroscience postdoctoral fellow, reported in Neuron that a protein in the complement pathway, called complement component 1q, or C1q, is abundant in the brain of preclinical models that mimic the tau pathology seen in Alzheimer’s and other neurodegenerative diseases. Manufactured and released by the brain’s immune cells, called microglia, research suggests C1q plays an essential role in neurodevelopmental synaptic pruning. But in tau pathologies, C1q may lead to the accelerated decay of synapses crucial for proper brain function. The team’s research suggests that C1q-blocking antibodies reduced the removal of synapses by microglia and rescued synapse density in mice. The study also found elevated C1q levels in the synapses of Alzheimer's patients, suggesting that the complement pathway is reactivated in neurodegenerative disease.
Taking the research a step further, a study led by Jesse Hanson and Tiffany Wu, published in August 2019 in Cell Reports, showed that blocking C3, another key protein in the same complement pathway, similarly rescued synapse density and neuron loss in mice with tau pathologies. The team also found that C3, like C1q, was expressed in the microglia of these mice and elevated in the synapses of Alzheimer’s patients.
Together, the studies offer encouraging evidence that targeting microglial synapse removal through the complement pathway might help slow the progression of Alzheimer’s and other tau-associated neurodegenerative diseases that appear later in life.
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This article was updated on 8/21/2019 to include information from the 8/20/2019 publication in Cell Reports,“Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy.”
*While Morgan Sheng was an employee at the time this article was published, he has since left Genentech.
**While Borislav Dejanovic was an employee at the time this article was published, he has since left Genentech.