β-Secretase-1 elevation in aged monkey and Alzheimer’s disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and β-amyloid accumulation

Authors

  • Yan Cai,

    1. Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, China
    2. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
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    • These authors contributed equally to this study.

  • Kun Xiong,

    1. Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, China
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    • These authors contributed equally to this study.

  • Xue-Mei Zhang,

    1. Department of Anatomy, Southern Illinois University School of Medicine at Carbondale, 1135 Lincoln Drive, 2069 Life Science III, Carbondale, IL 62901-6525, USA
    2. Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
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    • These authors contributed equally to this study.

  • 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 at Carbondale, 1135 Lincoln Drive, 2069 Life Science III, Carbondale, IL 62901-6525, 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 Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
    2. Department of Anatomy, Southern Illinois University School of Medicine at Carbondale, 1135 Lincoln Drive, 2069 Life Science III, Carbondale, IL 62901-6525, USA
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  • Yaping Chu,

    1. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
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  • Jeffrey H. Kordower,

    1. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
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  • Xiao-Xin Yan

    1. Department of Anatomy, Southern Illinois University School of Medicine at Carbondale, 1135 Lincoln Drive, 2069 Life Science III, Carbondale, IL 62901-6525, USA
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Xiao-Xin Yan, as above.
E-mail: xyan@siumed.edu

Abstract

Alzheimer’s disease (AD) is the most common dementia-causing disorder in the elderly; it may be related to multiple risk factors, and is characterized pathologically by cerebral hypometabolism, paravascular β-amyloid peptide (Aβ) plaques, neuritic dystrophy, and intra-neuronal aggregation of phosphorylated tau. To explore potential pathogenic links among some of these lesions, we examined β-secretase-1 (BACE1) alterations relative to Aβ deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 protein and β-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend for increased overall density among cases with greater plaque pathology. In double-labeling preparations, BACE1 IR colocalized with immunolabeling for Aβ but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra-axonal and extracellular Aβ IR among virtually all neuritic plaques, ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype markers (GABAergic, glutamatergic, cholinergic, or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near to or in direct contact with blood vessels. These findings suggest that plaque formation in AD or normal aged primates relates to a multisystem axonal pathogenesis that occurs in partnership with a potential vascular or metabolic deficit. The data provide a mechanistic explanation for why senile plaques are present preferentially near the cerebral vasculature.

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