NIIGATA — Researchers have identified a function of the amyloid precursor protein (APP) in protecting neurons by expelling nuclear debris resulting from DNA damage. This function is impaired in Alzheimer's disease.

The scientists conducted investigations using cultured cells, human induced pluripotent stem cell (iPSC)-derived neurons, mouse brains, and postmortem human Alzheimer's brain tissue. Godfried Dougnon, Assistant Professor, stated, "When nuclear damage occurs, wild-type APP co-localizes with nuclear-derived material near lysosome-associated molecules and facilitates the expulsion of this debris out of the cell."

Cells with reduced APP expression could not efficiently clear nuclear debris, nor could cells carrying familial Alzheimer's disease-associated APP mutations. These cells accumulated the material intracellularly. This accumulation was observed with increased expression of inflammatory markers and indicators of cell death. Inhibiting lysosomal function or molecules related to exocytosis eliminated the cytoprotective effects of wild-type APP.

In mouse brains, reducing APP expression increased neuronal vulnerability to nuclear damage. However, restoring wild-type APP in mouse brains decreased markers of DNA damage. Familial Alzheimer's disease-associated mutant APP did not provide the same protective effect in the mouse models. Postmortem human Alzheimer's brain tissue revealed an accumulation of nuclear-derived material within neurons. This tissue also showed reduced APP levels per neuron.

Professor Hideaki Matsui stated, "When this function is lost through reduced APP levels or disease-associated mutations, the resulting accumulation of nuclear waste could drive the neuroinflammation and neurodegeneration seen in AD." The study's findings were published in the Proceedings of the National Academy of Sciences.