Alzheimer's disease: Shank3a protein deficiency may contribute to cognitive decline

Research has already established a link between Alzheimer’s disease and weakened synaptic protein synthesis, but until now it was not known whether one of these faulty proteins interferes with communication between neurons. However, an international team of researchers has just identified that a deficiency of the Shank3a protein contributes to cognitive decline and exacerbates the manifestations of Alzheimer's disease. The discovery opens the way to a therapeutic avenue remaining to be explored to prevent or slow down this neurodegenerative condition. “We knew that this protein, very abundant at the synapses, is involved in Phelan-McDermid syndrome,” said Frédéric Calon, the researcher specializing in brain diseases at the Research Centre of the CHU de Québec—Université Laval. In children suffering from this rare genetic disorder, the loss of a copy of the gene that codes for the Shank3a protein impacts their cognitive functioning, causing developmental delay and intellectual disabilities. “This is what gave us the idea of exploring how Shank3a was affected in people with Alzheimer’s,” said Calon, who contributed to this international study, published in the Journal of Neuroscience. Cognitive tests The researchers began by using a brain bank created in the United States as part of a longitudinal study begun in 1993. They were thus able to compare the level of Shank3a in 18 people diagnosed with Alzheimer's and in 18 others who had not been affected. Result: This level was 30% to 50% lower in Alzheimer’s patients. “We also showed that there was a negative correlation between the level of Shank3a and the results obtained during cognitive tests carried out in the year preceding death,” reported Calon, specifying that the neurofibrillary tangles characteristic of Alzheimer’s were also more abundant in individuals who were Shank3a deficient. To ensure that the synaptic protein plays a role in the disease, the scientists formed three groups of genetically modified mice. In the first, they presented the main manifestations of Alzheimer's (neurofibrillary tangles and amyloid plaques). The second brought together mice producing 50% less Shank3a than normal mice. The third consisted of rodents crossing the particularities of the first two groups, the aim being to study the synergies between the two phenomena. “The mice resulting from this cross have less object recognition memory and more anxiety than the mouse models of Alzheimer’s. In addition, they produce more proteins which form amyloid plaques and more tau proteins responsible for neurofibrillary tangles.” Read: Aging with a healthy brain: How lifestyle changes could help prevent up to 40% of dementia cases The researchers were somewhat surprised to find that these behavioural and biochemical changes were very limited in mice presenting only with a deficiency in Shank3a compared to those that had the characteristics of Alzheimer's. “Shank3a deficiency therefore seems to contribute to cognitive decline by exacerbating the manifestations of the disease,” concluded the researchers. If the origin of this deficiency remains unknown, the discovery of Calon and his colleagues could nevertheless open the way to new therapeutic research. “If our hypothesis is correct, treatments to preserve the levels of Shank3a in the synapses could help prevent the appearance or progression of Alzheimer's. But we are still far from considering their application in humans,” he said. The other avenue to explore would be, “to see if Shank3a can be a biomarker of the disease. If we can go back in time and know when the deficiency of this protein manifests itself, we could then detect Alzheimer's early. We know how to diagnose the disease, but we still don’t know when it starts.” Read: Hormone replacement therapy and risk of dementia

Alzheimer's disease: Shank3a protein deficiency may contribute to cognitive decline

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