In Alzheimer's disease (AD), our brain's major communication hubs—called synapses—are lost, leading to dementia. This loss of synapses occurs in specific areas of our brain, in particular an area called hippocampus, where memory is formed and stored. A big question scientists are exploring is what makes synapses in the hippocampus vulnerable to damage and loss in AD. Interestingly, we know more about how synapse loss occurs in the healthy developing brain, as synapse loss is a normal developmental process that is required for proper brain wiring. The brain makes too many synapses during development that then need to be refined. A few years ago, our lab identified one of the key ways this normal synapse loss occurs in the developing brain. It involves a group of immune molecules called “complement,” where complement molecules (C1q and downstream C3) mark specific synapses to be pruned. Then, brain immune cells called microglia eliminate the complement-marked synapses. Without the complement marking of synapses, we found that the brain was left with excess synapses.
In the mature healthy adult brain, when the remodeling phase largely is over, this pruning pathway is mostly turned off; that is, we see few complement proteins and also less phagocytic microglia in these brain regions. Our recent results suggest that complement and microglia can act as improper mediators of synapse loss in early stages of AD. We show that blocking the complement pathway can lead to rescue of synapse loss in multiple models, using both genetic and antibody-mediated approaches. Thus, our results show complement and microglia as crucial components of synapse loss in the AD brain. Furthermore, our data suggest that this pathway potentially can be targeted therapeutically, although more research is under way to study this in detail.