A study by Bassem Hassan’s team (Inserm) at the Paris Brain Institute shows for the first time the direct link between two key mechanisms of Alzheimer’s disease: the amyloid precursor protein (APP) defect and the Wnt signalling defect. In collaboration with Marie Claude Potier’s team (CNRS), they also show a direct effect of this interaction on the production of amyloid, one of the proteins that becomes pathological in the disease. The results are published in eLife.
Mutations in the APP gene, which produces the amyloid precursor protein, are one of the main familial causes of Alzheimer’s disease. These share most of their clinical features with the sporadic forms of the disease, which account for 95% of cases. The biological mechanisms between the two forms should also share a number of similarities between the two forms. The study of the genetic forms is therefore essential for a better understanding of this pathology as a whole.
Results have been accumulating for years, in Alzheimer’s disease models and in patients, on another cell signalling pathway that is very important in brain development and physiology, the Wnt pathway. This pathway has been shown to be associated with both more severe and milder forms of the disease.
A study conducted by Bassem Hassan’s team (Inserm) looked at the link between these two pathways and how they interact in normal and pathological conditions in the case of Alzheimer’s disease.
Using the fruit fly (Drosophila melanogaster) and mouse neurons, the researchers show that APP is in fact a receptor for the Wnt pathway, and that there is therefore a direct link between these two mechanisms. Wnt regulates APP levels and the way APP is processed in neurons.
APP is the precursor of the amyloid-beta peptide, known to be one of the major pathological proteins in Alzheimer’s disease. In collaboration with Marie-Claude Potier’s team (CNRS), the researchers wanted to evaluate the impact of the interaction between Wnt and APP on the production of beta-amyloid. They thus confirmed that the regulation of APP levels by the Wnt pathway affects amyloid production.
Taken together, these results provide important insights into the pathological mechanisms of Alzheimer’s disease at the molecular level, and their consequences for the production of beta amyloid.
Source The amyloid precursor protein is a conserved Wnt receptor. Liu T, Zhang T, Nicolas M, Boussicault L, Rice H, Soldano A, Claeys A, Petrova I, Fradkin L, De Strooper B, Potier MC, Hassan BA.Elife. 2021 Sep 9;10:e69199.