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Amyloid plaque pathogenesis in 5XFAD mouse spinal cord: retrograde transneuronal modulation after peripheral nerve injury

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Abstract

The spinal cord is composed of distinct neuronal groups with well-defined anatomic connections. In some transgenic (Tg) models of Alzheimer’s disease (AD), amyloid plaques develop in this structure, although the underlying cellular mechanism remains elusive. We attempted to explore the origin, evolution, and modulation of spinal β-amyloid (Aβ) deposition using Tg mice harboring five familiar AD-related mutations (5XFAD) as an experiential model. Dystrophic neuritic elements with enhanced β-secretase-1 (BACE1) immunoreactivity (IR) appeared as early as 2 months of age, and increased with age up to 12 months examined in this study, mostly over the ventral horn (VH). Extracellular Aβ IR emerged and developed during this same period, site-specifically co-existing with BACE1-labeled neurites often in the vicinity of large VH neurons that expressed the mutant human APP. The BACE1-labeled neurites almost invariably colocalized with β-amyloid precursor protein (APP) and synaptophysin, and frequently with the vesicular glutamate transporter-1 (VGLUT). Reduced IR for the neuronal-specific nuclear antigen (NeuN) occurred in the VH by 12 months of age. In 8-month-old animals surviving 6 months after a unilateral sciatic nerve transection, there were significant increases of Aβ, BACE1, and VGLUT IR in the VN of the ipsilateral relative to contralateral lumbar spinal segments. These results suggest that extracellular Aβ deposition in 5XFAD mouse spinal cord relates to a progressive and amyloidogenic synaptic pathology largely involving presynaptic axon terminals from projection neurons in the brain. Spinal neuritic plaque formation is enhanced after peripheral axotomy, suggesting a retrograde transneuronal modulation on pathogenesis.

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Acknowledgments

This study was supported by the Illinois Department of Public Health (X.X.Y.), the National Natural Science Foundation of China (#81171091 to X.X.Y. and #81171160 to X.G.L), Hunan Natural Science Foundation (11jj5072 to J.M.L) and the intramural research program of National Institute on Aging, NIH (Z01-IAAG000944-04 to H.C.). We thank Elan Pharmaceuticals for providing the 3D6 antibody.

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  1. Neuroscience Research Center, Changsha Medical University, Changsha, 410219, Hunan, China

    Jian-Ming Li

  2. Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, 410013, Hunan, China

    Jian-Ming Li, Zhi-Qin Xue, Si-Hao Deng, Xue-Gang Luo, Yan Cai & Xiao-Xin Yan

  3. Department of Anatomy, Xinjiang Medical University, Ürümqi, 830011, Xinjiang, China

    Zhi-Qin Xue

  4. Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL, 62901, USA

    Peter R. Patrylo, Gregory W. Rose & Xiao-Xin Yan

  5. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA

    Huaibin Cai

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  1. Jian-Ming Li
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Li, JM., Xue, ZQ., Deng, SH. et al. Amyloid plaque pathogenesis in 5XFAD mouse spinal cord: retrograde transneuronal modulation after peripheral nerve injury. Neurotox Res 24, 1–14 (2013). https://doi.org/10.1007/s12640-012-9355-2

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