A protective role for APP in nuclear waste clearance via lysosomal exocytosis
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Godfried Dougnon
Department of Neuroscience of Disease, Brain Research Institute, Niigata University
Takayoshi Otsuka
The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut
Yuka Nakamura
Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University
Akiko Sakai
Department of Neuroscience of Disease, Brain Research Institute, Niigata University
Tomoyuki Yamanaka
Department of Neuroscience of Disease, Brain Research Institute, Niigata University
Noriko Matsui
Department of Neuroscience of Disease, Brain Research Institute, Niigata University
Asa Nakahara
Department of Pathology, Brain Research Institute, Niigata University
Ai Ito
Department of Neuroscience of Disease, Brain Research Institute, Niigata University
Atsushi Hatano
Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University
Masaki Matsumoto
Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University
Hironaka Igarashi
Department of Biological Magnetic Resonance, Center for Integrated Human Brain Science, Brain Research Institute, Niigata University
Akiyoshi Kakita
Department of Pathology, Brain Research Institute, Niigata University
Masaki Ueno
Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University
Hideaki Matsui
Department of Neuroscience of Disease, Brain Research Institute, Niigata University