Researchers at the Niigata University Brain Research Institute have discovered a new function for amyloid precursor protein (APP), a molecule long studied as a precursor to amyloid-β (Aβ) in Alzheimer’s disease (AD). This study demonstrates that APP actively protects neurons by expelling damaged nuclear material through a process called lysosomal exocytosis, providing a fundamentally new way of thinking about AD.
APP is best known as the protein whose enzymatic cleavage generates the Aβ peptide. Accumulation of Aβ in the brain is a hallmark of AD. However, the physiological function of full-length APP before cleavage is still not well understood. It is well established that aging, oxidative stress, and DNA damage compromise cell nuclear integrity and can leak nuclear contents, such as DNA fragments, chromatin, and histone proteins, into the cytoplasm. This “nuclear waste” can cause strong inflammatory responses and cell death, but the mechanisms by which neurons process this material are largely unknown.
The research team investigated the role of APP in nuclear damage protection using a comprehensive set of experimental models, including cultured cells, human iPSC-derived neurons, mouse brain, and postmortem human Alzheimer’s disease brain tissue.
When nuclear damage occurs, wild-type APP colocalizes with nuclear-derived material near lysosome-associated molecules and facilitates the export of this debris out of the cell. ”
Dr. Godfried Dagnon (first author, Assistant Professor, Department of Disease Neuroscience, Brain Research Institute, Niigata University)
Dr. Dagnon further explains that this clearance is dependent on lysosomal exocytosis. Lysosomal exocytosis is the fusion of lysosomes and cell membranes to release their contents outside the cell.
Crucially, cells with reduced APP expression or carrying familial AD-associated APP mutations were unable to efficiently remove nuclear waste and instead accumulated this material intracellularly. This accumulation was accompanied by increased expression of inflammatory markers and cell death indicators. Inhibiting lysosomal function or exocytosis-related molecules abolished the cytoprotective effects of wild-type APP.
In experiments in mouse brains, reducing APP makes neurons more susceptible to nuclear damage, while restoring wild-type APP reduces DNA damage markers. Remarkably, the familial AD-associated mutant APP failed to recapitulate this protection. Researchers observed accumulation of nuclear-derived material within neurons, abnormal nuclear morphology, and reduced levels of APP per neuron in postmortem human Alzheimer’s disease brain tissue. These findings are consistent with loss of APP-dependent nuclear waste clearance in disease.
“These findings prompt us to completely reconsider the role of APP,” says lead author Dr. Hideaki Matsui, a professor in the department. Professor Matsui explains, “APP is not only a source of harmful Aβ peptides, but also appears to be a cell guardian that removes nuclear debris under conditions of nuclear stress. When this function is lost due to reduced APP levels or disease-associated mutations, the resulting accumulation of nuclear waste may lead to the neuroinflammation and neurodegeneration seen in Alzheimer’s disease.”
The research team’s findings add a new dimension to the biology of Alzheimer’s disease, placing nuclear damage and lysosomal dysfunction as potential upstream contributors to disease pathology. Future studies will investigate how the nuclear waste removal function of APP is related to Aβ accumulation, and at what stages of aging and neurodegeneration this mechanism becomes dysfunctional.
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Reference magazines:
Dagnon, G. Others. (2026). Protective role of APP in nuclear waste removal via lysosomal exocytosis. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2524190123. https://www.pnas.org/doi/10.1073/pnas.2524190123
