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

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

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Pages (from-to)2271-2283
    Number of pages13
    JournalEuropean Journal of Neuroscience
    Volume30
    Issue number12
    DOIs
    StatePublished - Dec 2009

    Keywords

    • Aging
    • Axonopathy
    • Dystrophic neurite
    • Neuroplasticity
    • Secretase
    • Senile plaques

    ASJC Scopus subject areas

    • Neuroscience(all)

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