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β-Secretase-1 elevation in transgenic mouse models of Alzheimer’s disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development

Authors

  • Xue-Mei Zhang,

    1. Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA
    2. Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
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    • *

      These authors contributed equally to this work.

  • Yan Cai,

    1. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
    2. Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, China
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    • *

      These authors contributed equally to this work.

  • Kun Xiong,

    1. Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, China
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  • Huaibin Cai,

    1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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  • Xue-Gang Luo,

    1. Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, China
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  • Jia-Chun Feng,

    1. Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
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  • Richard W. Clough,

    1. Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA
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  • Robert G. Struble,

    1. Center for Alzheimer’s disease, Southern Illinois University School of Medicine, Springfield, IL, USA
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  • Peter R. Patrylo,

    1. Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA
    2. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
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  • Xiao-Xin Yan

    1. Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA
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Dr Xiao-Xin Yan, as above.
E-mail: xyan@siumed.edu

Abstract

The presence of neuritic plaques is a pathological hallmark of Alzheimer’s disease (AD). However, the origin of extracellular β-amyloid peptide (Aβ) deposits and the process of plaque development remain poorly understood. The present study attempted to explore plaque pathogenesis by localizing β-secretase-1 (BACE1) elevation relative to Aβ accumulation and synaptic/neuritic alterations in the forebrain, using transgenic mice harboring familial AD (FAD) mutations (5XFAD and 2XFAD) as models. In animals with fully developed plaque pathology, locally elevated BACE1 immunoreactivity (IR) coexisted with compact-like Aβ deposition, with BACE1 IR occurring selectively in dystrophic axons of various neuronal phenotypes or origins (GABAergic, glutamatergic, cholinergic or catecholaminergic). Prior to plaque onset, localized BACE1/Aβ IR occurred at swollen presynaptic terminals and fine axonal processes. These BACE1/Aβ-containing axonal elements appeared to undergo a continuing process of sprouting/swelling and dystrophy, during which extracellular Aβ IR emerged and accumulated in surrounding extracellular space. These data suggest that BACE1 elevation and associated Aβ overproduction inside the sprouting/dystrophic axonal terminals coincide with the onset and accumulation of extracellular amyloid deposition during the development of neuritic plaques in transgenic models of AD. Our findings appear to be in harmony with an early hypothesis that axonal pathogenesis plays a key or leading role in plaque formation.

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