More than 99% of clinical trials for Alzheimer’s drugs have failed, suggesting that our current knowledge of the mechanisms underlying Alzheimer's Disease (AD) is incomplete. This week, a group of scientist from MIT, Harvard, Stanford, and UCSF have identified an important new mechanism by which the synapses in the brain are lost in an animal model of AD. Dr. Beth Stevens, Ph.D., and team, found that a developmental process has gone awry, causing some immune cells (microglia) to "eat" (phagocytosize) the connections (synapses) between neurons. In the development of the brain, a protein called C1q sets off a series of chemical reactions that ultimately mark a synapse for destruction by microglia. The microglia are glial cells that have macrophage-like properties and are resident in the CNS. In the AD model, C1q is highly elevated.
Using two AD mouse models, each of which produces excess amounts of the β amyloid protein (a biomarker of AD), and develops memory and learning impairments as they age, she and her team found that both strains had elevated levels of C1q in brain tissue. When they used an antibody to block C1q from eliciting microglial-based destruction, however, synapse loss did not occur. Microglia only destroyed synapses when β amyloid was present, suggesting that the combination of protein and C1q is what destroys synapses, rather than either element alone.
Professor Stevens has helped to start a company to develop a monoclonal antibody to block C1q for the treatment of AD. However, one must be careful about interpreting these results for the sake of therapeutic development. Using animal models for disease, especially models that don't mimic the etiology of the disease, in this case a transgenic mouse, often don't translate well to the clinic. However, the basic science in these studies is excellent, and gives us very important clues about nervous system function, and one of the pathways that may have gone awry in Alzheimer's.