A protective role for APP in nuclear waste clearance via lysosomal exocytosis

Journal article

Godfried Dougnon*, Takayoshi Otsuka, Yuka Nakamura, Akiko Sakai, Tomoyuki Yamanaka, Noriko Matsui, Asa Nakahara, Ai Ito, Atsushi Hatano, Masaki Matsumoto, Hironaka Igarashi, Akiyoshi Kakita, Masaki Ueno, Hideaki Matsui
Proceedings of the National Academy of Sciences, vol. 123, 2026, pp. e2524190123

DOI: 10.1073/pnas.2524190123

Cite

APA Click to copy
Dougnon*, G., Otsuka, T., Nakamura, Y., Sakai, A., Yamanaka, T., Matsui, N., … Matsui, H. (2026). A protective role for APP in nuclear waste clearance via lysosomal exocytosis. Proceedings of the National Academy of Sciences, 123, e2524190123. https://doi.org/10.1073/pnas.2524190123

Chicago/Turabian Click to copy
Dougnon*, Godfried, Takayoshi Otsuka, Yuka Nakamura, Akiko Sakai, Tomoyuki Yamanaka, Noriko Matsui, Asa Nakahara, et al. “A Protective Role for APP in Nuclear Waste Clearance via Lysosomal Exocytosis.” Proceedings of the National Academy of Sciences 123 (2026): e2524190123.

MLA Click to copy
Dougnon*, Godfried, et al. “A Protective Role for APP in Nuclear Waste Clearance via Lysosomal Exocytosis.” Proceedings of the National Academy of Sciences, vol. 123, 2026, p. e2524190123, doi:10.1073/pnas.2524190123.

BibTeX Click to copy

@article{dougnon2026a,
  title = {A protective role for APP in nuclear waste clearance via lysosomal exocytosis},
  year = {2026},
  journal = {Proceedings of the National Academy of Sciences},
  pages = {e2524190123},
  volume = {123},
  doi = {10.1073/pnas.2524190123},
  author = {Dougnon*, Godfried and Otsuka, Takayoshi and Nakamura, Yuka and Sakai, Akiko and Yamanaka, Tomoyuki and Matsui, Noriko and Nakahara, Asa and Ito, Ai and Hatano, Atsushi and Matsumoto, Masaki and Igarashi, Hironaka and Kakita, Akiyoshi and Ueno, Masaki and Matsui, Hideaki}
}

Amyloid precursor protein (APP) is widely known for its role in Alzheimer’s disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear waste material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.