Evidence of Aβ- and transgene-dependent defects in ERK-CREB signaling in Alzheimer’s models

Authors

  • Qiu-Lan Ma,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Marni E. Harris-White,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Oliver J. Ubeda,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Mychica Simmons,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Walter Beech,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Giselle P. Lim,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Bruce Teter,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Sally A. Frautschy,

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Department of Neurology, University of California, Los Angeles, California, USA
    3. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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  • Greg M. Cole

    1. Department of Medicine, University of California, Los Angeles, California, USA
    2. Department of Neurology, University of California, Los Angeles, California, USA
    3. Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, VA Medical Center, North Hills, California, USA
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Address correspondence and reprint requests to Greg. M. Cole, Greater Los Angeles Veterans Affairs Healthcare System, Alzheimer Research-151, Building 7, Room A101, 16111 Plummer Street North Hills, CA 91343, USA. E-mail: gmcole@ucla.edu

Abstract

Extracellular-signal regulated kinase (ERK) signaling is critical for memory and tightly regulated by acute environmental stimuli. In Alzheimer disease transgenic models, active ERK is shown to first be increased, then later reduced, but whether these baseline changes reflect disruptions in ERK signaling is less clear. We investigated the influence of the familial Alzheimer’s disease transgene APPsw and β-amyloid peptide (Aβ) immunoneutralization on cannulation injury-associated (i.c.v. infusion) ERK activation. At both 12 and 22 months of age, the trauma-associated activation of ERK observed in Tg mice was dramatically attenuated in Tg+. In cortices of 22-month-old non-infused mice, a reduction in ERK activation was observed in Tg+, relative to Tg mice. Intracerebroventricular (i.c.v.) anti-Aβ infusion significantly increased phosphorylated ERK, its substrate cAMP-response element-binding protein (CREB) and a downstream target, the NMDA receptor subunit. We also demonstrated that Aβ oligomer decreased active ERK and subsequently active CREB in human neuroblastoma cells, which could be prevented by oligomer immunoneutralization. Aβ oligomers also inhibited active ERK and CREB in primary neurons, in addition to reducing the downstream post-synaptic protein NMDA receptor subunit. These effects were reversed by anti-oligomer. Our data strongly support the existence of an APPsw transgene-dependent and Aβ oligomer-mediated defect in regulation of ERK activation.

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