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Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation

Author

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  • Demian Obregon

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
    James A. Haley Veterans' Hospital, Tampa 33612, Florida, USA.)

  • Huayan Hou

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.)

  • Juan Deng

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.)

  • Brian Giunta

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
    Neuroimmunology Laboratory, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.)

  • Jun Tian

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.)

  • Donna Darlington

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.)

  • Md Shahaduzzaman

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
    Center for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.)

  • Yuyuan Zhu

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.)

  • Takashi Mori

    (Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama 350-8550, Japan.)

  • Mark P. Mattson

    (Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore 21224, Maryland, USA.)

  • Jun Tan

    (Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
    James A. Haley Veterans' Hospital, Tampa 33612, Florida, USA.)

Abstract

In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-β (Aβ) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aβ generation by directly associating with β-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aβ production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases β-amyloid plaques and soluble Aβ. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aβ-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.

Suggested Citation

  • Demian Obregon & Huayan Hou & Juan Deng & Brian Giunta & Jun Tian & Donna Darlington & Md Shahaduzzaman & Yuyuan Zhu & Takashi Mori & Mark P. Mattson & Jun Tan, 2012. "Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation," Nature Communications, Nature, vol. 3(1), pages 1-9, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1781
    DOI: 10.1038/ncomms1781
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