Does complement cascade-mediated synapse elimination drive cognitive decline in the aging brain?

2011 senior Scholar Award in aging

The decline of cognitive function is one of the greatest health threats for the aged population. It has been widely accepted that mainly loss of synaptic connections, rather than loss of neurons, is responsible for age-associated cognitive impairment. However the molecular mechanisms underlying this age-related decline are unknown. A vast loss of synapses not only occurs in the aging brain but also within the normal developing brain as neural circuits are sculpted. Our previous experiments unexpectedly identified an immune system pathway, called the classical complement cascade, as a critical mediator of synapse elimination in the developing central nervous system. We found that C1q, the initiation protein of this cascade, binds to developing synapses throughout the brain, where it triggers the activation of the complement cascade leading to deposition of the critical complement protein C3, which tags synapses for phagocytosis and elimination.

In this project, we will investigate the role of C1q and other complement cascade proteins in normal brain aging. Specifically we will test the hypothesis that the complement cascade mediates normal developmental synapse elimination and that its increased activation in the aging brain leads to excessive synapse loss which in turn results in aging-related cognitive decline.

Specifically, in order to address this hypothesis, we will ask:

1. Does C1q deposit on aging hippocampal synapses and if so, does it deposit on specific types of synapses? We will use immunoelectron microscopy and array tomography.
2. Does the classical complement cascade get activated at aging synapses? We will characterize whether other complement components downstream of C1q accumulate in the aging hippocampus and deposit on synapses.
3. Is C1q required for aging related synapse loss and cognitive decline? We will conduct behavioral analyses of C1q knockout mice, comparing their cognition and memory to their wild type littermates. We will also conduct electrophysiological analyses of aged hippocampus.
4. Does classical complement cascade activation similarly increase in aging human brain? We will perform and compare Western blotting and immunostaining on human hippocampus from young and old brains.

If the classical complement cascade mediates causes excessive synapse loss in the aging brain and is responsible for aging-related cognitive decline, it represents and important new therapeutic target for neuroenhancement in an aging population.