Additional insight into how brain-cell connections, or synapses, are lost early in Alzheimer’s disease has been gained from research by HMS researchers at Boston Children’s Hospital. In their March 31 online report in Science, the scientists show that the process starts before telltale plaques accumulate in the brain and suggest new therapeutic targets to preserve cognitive function during the early stages of the disease.
Led by senior author Beth Stevens, an HMS assistant professor of neurology in the F.M. Kirby Neurobiology Center at Boston Children’s, and first author Soyon Hong, an HMS research fellow in neurology at Boston Children’s, the researchers show in multiple mouse models of Alzheimer’s that mechanisms similar to those used to prune excess synapses in the healthy developing brain become activated later in life, when they shouldn’t be. By blocking these mechanisms, the researchers were able to reduce synapse loss in the mice.
Currently, there are five FDA-approved drugs for Alzheimer’s, but these boost cognition only temporarily and do not address the root causes of cognitive impairment in Alzheimer’s. Many drugs in development aim to eliminate amyloid plaque deposits or reduce inflammation in the brain. This study suggests, however, that Alzheimer’s could be targeted much earlier, before those pathologic changes occur.
“Synapse loss is a strong correlate of cognitive decline,” says Stevens, noting that such loss also occurs in frontotemporal dementia, Huntington’s disease, schizophrenia, glaucoma, and other conditions.
In the mouse models, the team showed that synapse loss requires the activation of a protein called C1q, which tags synapses for elimination. Microglia, which are immune cells in the brain, then “eat” the synapses, similar to what occurs during normal brain development. In the mice, C1q became more abundant around vulnerable synapses before amyloid plaque deposits could be observed. But when the scientists blocked either C1q, a downstream protein called C3, or the C3 receptor on microglia, synapse loss did not occur.
Image: Soyon Hong