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@ARTICLE{Liu:153452,
      author       = {Liu, Dan and Zhao, Yujia and Qi, Yuze and Gao, Yun and Tu,
                      Dezhen and Wang, Yinxi and Gao, Hui-Ming and Zhou, Qihui},
      title        = {{B}enzo(a)pyrene exposure induced neuronal loss, plaque
                      deposition, and cognitive decline in {APP}/{PS}1 mice},
      journal      = {Journal of neuroinflammation},
      volume       = {17},
      number       = {1},
      issn         = {1742-2094},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2020-01449},
      pages        = {258},
      year         = {2020},
      abstract     = {BackgroundExposure to benzo(a)pyrene (BaP) was associated
                      with cognitive impairments and some Alzheimer’s disease
                      (AD)-like pathological changes. However, it is largely
                      unknown whether BaP exposure participates in the disease
                      progression of AD.ObjectivesTo investigate the effect of BaP
                      exposure on AD progression and its underlying
                      mechanisms.MethodsBaP or vehicle was administered to
                      4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and
                      wildtype (WT) mice for 2 months. Learning and memory
                      ability and exploratory behaviors were evaluated 1 month
                      after the initiation/termination of BaP exposure. AD-like
                      pathological and biochemical alterations were examined
                      1 month after 2-month BaP exposure. Levels of soluble
                      beta-amyloid (Aβ) oligomers and the number of Aβ plaques
                      in the cortex and the hippocampus were quantified. Gene
                      expression profiling was used to evaluate alternation of
                      genes/pathways associated with AD onset and progression.
                      Immunohistochemistry and Western blot were used to
                      demonstrate neuronal loss and neuroinflammation in the
                      cortex and the hippocampus. Treatment of primary neuron-glia
                      cultures with aged Aβ (a mixture of monomers, oligomers,
                      and fibrils) and/or BaP was used to investigate mechanisms
                      by which BaP enhanced Aβ-induced
                      neurodegeneration.ResultsBaP exposure induced progressive
                      decline in spatial learning/memory and exploratory behaviors
                      in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer
                      behavioral deficits than WT mice. Moreover, BaP exposure
                      promoted neuronal loss, Aβ burden and Aβ plaque formation
                      in APP/PS1 mice, but not in WT mice. Gene expression
                      profiling showed most robust alteration in genes and
                      pathways related to inflammation and immunoregulatory
                      process, Aβ secretion and degradation, and synaptic
                      formation in WT and APP/PS1 mice after BaP exposure.
                      Consistently, the cortex and the hippocampus of WT and
                      APP/PS1 mice displayed activation of microglia and astroglia
                      and upregulation of inducible nitric oxide synthase (iNOS),
                      glial fibrillary acidic protein (GFAP), and NADPH oxidase
                      (three widely used neuroinflammatory markers) after BaP
                      exposure. Furthermore, BaP exposure aggravated
                      neurodegeneration induced by aged Aβ peptide in primary
                      neuron-glia cultures through enhancing NADPH oxidase-derived
                      oxidative stress.ConclusionOur study showed that chronic
                      exposure to environmental pollutant BaP induced,
                      accelerated, and exacerbated the progression of AD, in which
                      elevated neuroinflammation and NADPH oxidase-derived
                      oxidative insults were key pathogenic events.},
      keywords     = {Alzheimer Disease: pathology / Amyloid beta-Protein
                      Precursor: genetics / Animals / Behavior, Animal: drug
                      effects / Benzo(a)pyrene: toxicity / Cognitive Dysfunction:
                      chemically induced / Cognitive Dysfunction: pathology /
                      Disease Models, Animal / Exploratory Behavior: drug effects
                      / Maze Learning: drug effects / Mice / Neurons: drug effects
                      / Neurons: pathology / Plaque, Amyloid: pathology /
                      Presenilin-1: genetics / Spatial Memory: drug effects},
      cin          = {AG Breteler},
      ddc          = {610},
      cid          = {I:(DE-2719)1012001},
      pnm          = {345 - Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC7461337},
      pubmed       = {pmid:32867800},
      doi          = {10.1186/s12974-020-01925-y},
      url          = {https://pub.dzne.de/record/153452},
}