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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 function remains 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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272590 | GEO | 2026/06/11

REPOSITORIES: GEO

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

Project description: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 function remains 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 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.

2026-06-11 | PXD053992 | Pride

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

2026-06-11 | PXD053993 | Pride

Misprocessing of APP and accumulation of β-Amyloid causes early alteration of pathways implicated in late-onset Alzheimer disease.

Project description:Genome-wide association studies (GWAS) have identified genes in lipid metabolism,inflammation and vesicular trafficking pathways as risk factors for late onset Alzheimer disease (LOAD). The mechanism by which they cause AD and their relationship to the amyloid cascade affected by genes causing early onset familial AD is unknown. Unproven hypotheses are that these LOAD genes modulate the amyloid cascade itself or downstream targets affected by this cascade.If so, it is likely that these genes and/or other genes in the same pathways may show alterations in their expression as an early consequence of misprocessing of amyloid precursor protein (APP) and accumulation of amyloid β-peptides (Aβ). We report that in three independent APP transgenic mouse models of AD, multiple genes in lipid and inflammation pathways show very early changes in mRNA and protein expression. Many of these changes are reversed by treatment with LXR agonists, which regulate transcription of genes in lipid/inflammation pathways, and which we have previously shown can reverse the cognitive deficits and neuropathology in Tg2756 mice. These results suggest that changes in lipid and inflammation pathways are likely to be very early consequences of APP misprocessing and Aβ accumulation in AD. Moreover, genetic variants within these pathways might affect risk for AD by modulating this early response. These pathways are likely to contain biomarkers of early disease and targets for therapies. TgCRND8 mice and wild-type littermate controls at ages 70, 80, and 150 days (n = 4 mice per cohort) were used in the study.

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