Key Alzheimer's protein actively protects neurons from nuclear damage

Researchers at Niigata University's Brain Research Institute have uncovered a new function of amyloid precursor protein (APP), a molecule long studied as the precursor to amyloid-β (Aβ) in Alzheimer's disease (AD). The study demonstrates that APP actively protects neurons by expelling damaged nuclear material through a process called lysosomal exocytosis - offering a fundamentally new way of thinking about AD.

APP is best known as the protein from which Aβ peptides are generated through enzymatic cleavage; Aβ accumulation in the brain is a hallmark of AD. However, the physiological functions of full-length APP before cleavage have remained poorly understood. It is well established that aging, oxidative stress, and DNA damage can compromise the integrity of the cell nucleus, causing nuclear contents - including DNA fragments, chromatin, and histone proteins - to leak into the cytoplasm. This "nuclear waste" can trigger potent inflammatory responses and cell death, yet the mechanisms by which neurons dispose of this material have been largely unknown.

The research team used a comprehensive set of experimental models, including cultured cells, human iPSC-derived neurons, mouse brains, and postmortem human AD brain tissue, to investigate APP's role in nuclear damage defense.

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."