Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex

Xue Mei Zhang, Kun Xiong, Yan Cai, Huaibin Cai, Xue Gang Luo, Jia Chun Feng, Richard W. Clough, Peter R. Patrylo, Robert G. Struble, Xiao Xin Yan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Cerebral hypometabolism and amyloid accumulation are principal neuropathological manifestations of Alzheimer's disease (AD). Whether and how brain/neuronal activity might modulate certain pathological processes of AD are interesting topics of recent clinical and basic research in the field, and may be of potential medical relevance in regard to both the disease etiology and intervention. Using the Tg2576 transgenic mouse model of AD, this study characterized a promotive effect of neuronal hypoactivity associated with functional deprivation on amyloid plaque pathogenesis in the olfactory pathway. Unilateral naris-occlusion caused β-secretase-1 (BACE1) elevation in neuronal terminals in the deprived relative to the non-deprived bulb and piriform cortex in young adult mice. In parallel with the overall age-related plaque development in the forebrain, locally increased BACE1 immunoreactivity co-occurred with amyloid deposition first in the piriform cortex then within the bulb, more prominent on the deprived relative to the non-deprived side. Biochemical analyses confirmed elevated BACE1 protein levels, enzymatic activity and products in the deprived relative to non-deprived bulbs. Plaque-associated BACE1 immunoreactivity in the bulb and piriform cortex was localized preferentially to swollen/sprouting glutamatergic axonal terminals, with Aβ immunoreactivity occurring inside as well as around these terminals. Together, these findings suggest that functional deprivation or neuronal hypoactivity facilitates amyloid plaque formation in the forebrain in a transgenic model of AD, which operates synergistically with age effect. The data also implicate an intrinsic association of amyloid accumulation and plaque formation with progressive axonal pathology.

    Original languageEnglish (US)
    Pages (from-to)710-721
    Number of pages12
    JournalEuropean Journal of Neuroscience
    Volume31
    Issue number4
    DOIs
    StatePublished - Feb 2010

    Keywords

    • Amyloidogenesis
    • Axonal pathology
    • Cerebral hypometabolism
    • Neuroplasticity
    • Secretase

    ASJC Scopus subject areas

    • Neuroscience(all)

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