An age-related axon terminal pathology around the first olfactory relay that involves amyloidogenic protein overexpression without plaque formation

Y. Cai, Z. Q. Xue, X. M. Zhang, M. B. Li, H. Wang, X. G. Luo, H. Cai, X. X. Yan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The glomeruli are the first synaptic relay on the olfactory pathway and play a basic role in smell perception. Glomerular degeneration occurs in humans with age and in Alzheimer's disease (AD). The glomeruli heavily express β-amyloid precursor protein (APP), β-secretase (BACE1) and γ-secretase complex. However, extracellular β-amyloid peptide (Aβ) deposition occurs fairly rarely at this location in postmortem pathological studies. We sought to explore age-related glomerular changes that might link to alteration in amyloidogenic proteins and/or plaque pathogenesis in transgenic models of AD and humans. Focally increased BACE1 immunoreactivity (IR) in the glomerular layer was identified in several transgenic models, and characterized systematically in transgenic mice harboring five familiar AD-related mutations (5XFAD). These elements were co-labeled with antibodies against APP N-terminal (22C11) and Aβ N-terminal (3D6, 6E10) and mid-sequence (4G8). They were not co-labeled with two Aβ C-terminal antibodies (Ter40, Ter42), nor associated with extracellular amyloidosis. These profiles were further characterized to be most likely abnormal olfactory nerve terminals. Reduced glomerular area was detected in 6-12-month-old 5XFAD mice relative to non-transgenic controls, and in aged humans relative to young/adult controls, more robust in AD than aged subjects without cerebral amyloid and tau pathologies. The results suggest that olfactory nerve terminals may undergo age-related dystrophic and degenerative changes in AD model mice and humans, which are associated with increased labeling for amyloidogenic proteins but not local extracellular Aβ deposition. The identified axon terminal pathology might affect neuronal signal transmission and integration at the first olfactory synaptic relay.

    Original languageEnglish (US)
    Pages (from-to)160-173
    Number of pages14
    JournalNeuroscience
    Volume215
    DOIs
    StatePublished - Jul 26 2012

    Keywords

    • Aging
    • Amyloidogenesis
    • Axonal pathology
    • Dementia
    • Olfactory deficit

    ASJC Scopus subject areas

    • Neuroscience(all)

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