Crucial role of the Alzheimer protein APP outside the brain

For decades, APP biology has been framed almost entirely through the lens of amyloid plaques, neurodegeneration, and Alzheimer pathology. In a study recently published in Science Advances we now show that APP promotes an endogenous tissue repair system that promotes heart repair after myocardial infarction. Following myocardial infarction, the formation of new blood vessels is crucial for the regeneration of damaged heart tissue. In a collaborative project with Prof. Dr. Stefan Offermanns and Dr. Haruya Kawase from the Max Planck Institute for Heart and Lung Research, we demonstrate that the proteins APP and APLP2 - previously known primarily from Alzheimer’s disease - play a central role in this repair process. Using genetic mouse models, we demonstrate that the absence of APP and APLP2 in endothelial cells leads to impaired angiogenesis, worsened heart failure, and increased mortality following a myocardial infarction. In contrast, the targeted expression of APPsα in endothelial cells was able to compensate for these defects. Under oxygen deprivation, such as that occurring after a heart attack, APP and APLP2 are proteolytically processed and secreted by endothelial cells into the soluble fragments APPsα and APLP2sα. These fragments bind to the endothelial receptor tyrosine kinase KIT, acting as positive allosteric modulators and thereby promoting angiogenesis and repair of the damaged tissue. This work identifies for the first time a functional receptor mechanism for secreted APPsα and APLP2sα fragments outside the brain and opens up new perspectives for regenerative therapies following ischemia.