Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer’s pathogenesis

Sep 15, 2025Alzheimer's research & therapy

Lower Ap1s1 levels in the aging brain increase nerve cell vulnerability to amyloid-beta and oxidative stress in Alzheimer's development

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Abstract

Eight genes were found to be downregulated in both aging and Alzheimer's disease datasets.

Reduced expression of the adaptor protein complex 1 sigma 1 subunit () was validated in various mouse models of dementia.
Ap1s1 knockdown induced cellular aging without directly affecting cell viability.
Silencing Ap1s1 increased neuronal sensitivity to oxidative stress and amyloid-beta toxicity, leading to reduced cell survival.
Proteomic analysis after Ap1s1 depletion indicated disruptions in ribosomal RNA modifications and Golgi-associated vesicle formation.
These findings suggest Ap1s1 plays a significant role in both brain aging and the development of Alzheimer's disease.

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Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and memory impairment. Brain aging is indisputably the most significant risk factor for AD. Given that aging is a fundamental driving force behind the onset of AD, identifying the aging - regulated genes that contribute to AD development is of utmost importance. Such genes might hold the key to preventing AD or delaying the transition from normal aging to the disease state. In the present study, a comprehensive bioinformatic analysis was conducted on brain transcriptomic datasets obtained from both aging individuals and those with Alzheimer's disease. Among the shared differentially expressed genes, eight genes were found to be downregulated in both aging and AD datasets. Notably, reduced expression of adaptor protein complex 1 sigma 1 subunit () was validated across multiple mouse models with varying degree of dementia, including aged mice, senescence-accelerated SAMP8 mice, 5xFAD amyloidosis mice, as well as cellular models, including senescent Neuro-2a (N2a) cells, and Aβ-treated or expressing N2a neurons. Functional studies revealed that Ap1s1 knockdown induced cellular senescence without directly impairing viability. However, Ap1s1 silencing exacerbated neuronal vulnerability to oxidative stress (H₂O₂) and Aβ toxicity, manifesting as Golgi-dispersion and reduced survival. Proteomic profiling following Ap1s1 depletion implicated dysregulation of rRNA modifications in the nucleus and cytosol, Golgi-associated vesicle biogenesis. These findings position Ap1s1 as a critical aging-related gene at the nexus of brain aging and AD pathogenesis, whose decline may predispose neurons to Alzheimer's-related insults. As such, Ap1s1 may represent a potential therapeutic target for mitigating aging-related cognitive decline and delaying the onset of AD.

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Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer’s pathogenesis

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