Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aβ1-42 production in N2a-APPswe cells

Chunli Zou; Tingting Yang; Xinfeng Huang; Xiaohu Ren; Chen Yang; Benhong Xu; Jianjun Liu

doi:10.1016/j.heliyon.2024.e26832

Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aβ1-42 production in N2a-APPswe cells

Heliyon. 2024 Feb 21;10(8):e26832. doi: 10.1016/j.heliyon.2024.e26832. eCollection 2024 Apr 30.

Authors

Chunli Zou^{1

2}, Tingting Yang^{1

2}, Xinfeng Huang², Xiaohu Ren², Chen Yang², Benhong Xu², Jianjun Liu^{1

2}

Affiliations

¹ College of Public Health, Zunyi Medical University, Zunyi, 563000, China.
² Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518000, China.

Abstract

Alzheimer's disease is the most common form of dementia and is characterized by cognitive impairment. The disruption of autophagosome-lysosome function has been linked to the pathogenesis of Alzheimer's disease. Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphorus flame retardant that has the potential to cause neuronal damage. We found that TDCIPP significantly increased the expression of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), presenilin-1 (PS1) and Aβ42. Proteomic studies with TMT labeling revealed changes in the profiles of N2a-APPswe cells after exposure to TDCIPP. Proteomic and bioinformatics analyses revealed that lysosomal proteins were dysregulated in N2a-APPswe cells after treatment with TDCIPP. The LC3, P62, CTSD, and LAMP1 levels were increased after TDCIPP exposure, and dysregulated protein expression was validated by Western blotting. The exposure to TDCIPP led to the accumulation of autophagosomes, and this phenomenon was enhanced in the presence of chloroquine (CQ). Our results revealed for the first time that TDCIPP could be a potential environmental risk factor for AD development. The inhibition of autophagosome-lysosome fusion may have a significant impact on the generation of Aβ1-42 in response to TDCIPP.

Keywords: Alzheimer's disease; Autophagy; Aβ42; TDCIPP.