A multi-institutional team led by researchers at the Baylor College of Medicine published a study (“cindr, the Drosophila Homolog of the CD2AP Alzheimer’s Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis”) in Cell Reports that sheds new light on how the CD2AP gene may enhance Alzheimer’s disease susceptibility.
Integrating experiments in fruit flies, mice, and human brains, the scientists found that the CD2AP gene is involved in synaptic transmission. They also discovered that CD2AP affects neuronal communication by regulating the levels of key regulatory proteins present at synapses.
“The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin-binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release,” the investigators wrote.
“cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.”
Joshua Shulman, MD, PhD, associate professor of neurology at Baylor and corresponding author of the work, explained that the team first worked with the laboratory fruit fly to test the effect of deleting the gene in the brain. The researchers deleted the fly equivalent of the human CD2AP gene (cindr) and observed evidence of defective synapse structure and function. They also found that certain proteins accumulated more in the synapses of mutant flies.
Among the accumulated proteins were several that regulate neural communication. To connect these findings with Alzheimer’s disease, Shulman and his colleagues also studied a mouse in which the CD2AP gene was deleted and discovered brain changes similar to those they had found in flies. Finally, in order to establish relevance for humans, they examined a collection of more than 800 brain autopsies. Shulman and colleagues found that low CD2AP levels significantly correlated with abnormal turnover of synaptic proteins, and this relationship was enhanced in the setting of Alzheimer’s disease.