The NOVA Medical School research group in “Neuronal Trafficking in Aging”, led by Cláudia Almeida, has made a discovery impacting the understanding of the pathobiology of late-onset Alzheimer’s Disease. The study, recently published in Journal of Neuroscience, revealed that the gene CD2AP, identified as a genetic risk factor for the disease’s development, plays an essential role in the structure and function of synapses – contact points for communication between neurons - that are fundamental for maintaining neuronal functions such as memory.
Previous studies indicate that synapse loss in neurons begins around 20 years before the clinical manifestation of Alzheimer’s Disease, but the responsible mechanism was unknown. In addition to lifestyle, several genetic risk factors are known to increase the predisposition to Alzheimer’s, with the CD2AP gene being one of the most significant. However, it was still unclear whether the loss of function of this gene could affect synapses.
The NOVA Medical School team discovered that the loss of CD2AP function leads to reduced synapse formation and neuronal activity, an effect due to morphological changes in dendritic spines. These are projections formed on dendrites – parts of neuron structure - that function as "mini-antennas" to receive information from other neurons.
The research group also found that without CD2AP, the actin cytoskeleton of the dendritic spine - which provides shape and support to this critical structure for neuron-to-neuron communication - becomes compromised, leading to the elimination of dendritic spines and synapses. Furthermore, it was demonstrated that a mutation in CD2AP gene, identified in Alzheimer’s patients, similarly interferes with normal synaptic function.
Overall, the study’s findings help explain how variants of the CD2AP gene may increase the risk of synapse loss, and thus, contribute to the development of Alzheimer’s Disease. "Only by understanding how variants in our genomes increase the chance of developing the disease can we create personalized treatments for those who carry this genetic risk factor," explains Cláudia Almeida, the study coordinator. “We know that synapse loss occurs long before the disease manifests, so preventing this loss may be a way to treat the disease,” adds the researcher.
In the future, the team of scientists intends to study how synapses can be protected from the loss of CD2AP function. “We have already proven that in vitro gene therapy works in mouse neurons; next, we want to investigate more complex systems, such as human neurons and other models that allow us to replicate various stages of the disease, thus enabling us to understand the communication between different brain cell types that leads to the spread of disease toxicity,” Cláudia Almeida explains.