Researchers at Niigata University's Brain Research Institute announced on June 17 that they have discovered a new function of amyloid precursor protein (APP), a molecule widely studied as the precursor to amyloid-β in Alzheimer's disease. The study shows that APP actively protects neurons by expelling damaged nuclear material through lysosomal exocytosis, which may change current understanding of Alzheimer's disease.
APP is primarily known as the source of amyloid-β peptides, whose accumulation in the brain is a hallmark of Alzheimer's disease. However, the physiological roles of full-length APP before its cleavage have remained unclear. Aging, oxidative stress, and DNA damage can compromise cell nuclei, causing DNA fragments and other nuclear contents to leak into the cytoplasm. This "nuclear waste" can provoke inflammatory responses and cell death, but how neurons dispose of such material has not been well understood.
The research team used various experimental models—including cultured cells, human iPSC-derived neurons, mouse brains, and postmortem human Alzheimer’s brain tissue—to examine APP's role in defending against nuclear damage. Dr. Dougnon said this clearance process depends on lysosomal exocytosis: "the fusion of lysosomes with the cell membrane to release their contents extracellularly." Cells with reduced APP expression or familial Alzheimer’s-associated mutations failed to clear nuclear waste efficiently and accumulated it within cells; this was linked with increased inflammatory markers and indicators of cell death. Inhibiting lysosomal function or molecules related to exocytosis removed wild-type APP's protective effects.
In experiments with mouse brains, reducing APP made neurons more susceptible to nuclear damage while restoring wild-type APP reduced DNA damage markers. Familial Alzheimer’s-associated mutant forms did not replicate this protection. In postmortem human Alzheimer’s tissue, researchers found buildup of nuclear-derived material inside neurons along with abnormal nuclear morphology and lower levels of neuronal APP—consistent with loss of this protective mechanism in disease.
"These findings invite us to reconsider APP's role entirely," said senior author Dr. Hideaki Matsui, Professor at Niigata University Brain Research Institute. Professor Matsui added, "Rather than only being a source of harmful Aβ peptides, APP appears to be a cellular guardian that removes nuclear debris under conditions of nuclear stress. 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 team concluded that their results highlight new potential contributors to Alzheimer’s pathology involving both nuclear damage and lysosomal dysfunction.
