Researchers at Niigata University's Brain Research Institute have identified a previously unknown function of the amyloid precursor protein (APP) in protecting neurons by expelling damaged nuclear material from the cell.
Background
APP is known as the precursor to amyloid-β (Aβ) peptides, whose accumulation is a hallmark of Alzheimer's disease (AD). The physiological functions of full-length APP prior to cleavage have not been well understood.
Under conditions such as aging, oxidative stress, or genetic instability, the nuclear membrane can rupture, allowing nuclear contents—including DNA fragments, chromatin, and histone proteins—to leak into the cytoplasm, triggering inflammation and cell death. The mechanisms by which neurons dispose of this material have been largely unknown.
Key Findings
The study, published in PNAS (DOI: 10.1073/pnas.2524190123), used multiple experimental models including cultured cells, human iPSC-derived neurons, mouse brains, and postmortem human AD brain tissue.
- When nuclear damage occurs, wild-type APP co-localizes with nuclear-derived material near lysosome-associated molecules and facilitates the expulsion of this debris via lysosomal exocytosis, a process where lysosomes fuse with the cell membrane to expel waste.
- Cells with reduced APP expression or familial AD-associated APP mutations failed to clear nuclear waste efficiently, leading to intracellular accumulation, increased inflammatory markers, and cell death indicators.
- Inhibiting lysosomal function or exocytosis-related molecules abolished wild-type APP's cytoprotective effects.
- In mouse brain experiments, reducing APP levels increased neuronal vulnerability to nuclear damage. Restoring wild-type APP reduced DNA damage markers, while familial AD-associated mutant APP did not replicate this protection.
- In postmortem human AD brain tissue, researchers observed accumulation of nuclear-derived material within neurons, abnormal nuclear morphology, and reduced APP levels per neuron.
Researcher Statements
First author Dr. Godfried Dougnon 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."
Senior author Dr. Hideaki Matsui commented: "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, the resulting accumulation of nuclear waste could drive the neuroinflammation and neurodegeneration seen in AD."
Implications
The findings position nuclear damage and impaired waste clearance as potential upstream contributors to AD pathology. Future research will examine the relationship between APP's nuclear waste clearance function and Aβ accumulation, as well as determine at what stage during aging and neurodegeneration this mechanism fails.