• Open Access

Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease β-amyloid production

Authors

  • Kavon Rezai-Zadeh,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    Search for more papers by this author
  • R. Douglas Shytle,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    2. Center for Excellence in Aging and Brain Repair, Department of Neurosurgery University of South Florida, Tampa, FL, USA
    Search for more papers by this author
  • Yun Bai,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    Search for more papers by this author
  • Jun Tian,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    Search for more papers by this author
  • Huayan Hou,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    Search for more papers by this author
  • Takashi Mori,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    2. Institute of Medical Science, Saitama Medical Center/University Kawagoe, Saitama, Japan
    Search for more papers by this author
  • Jin Zeng,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    Search for more papers by this author
  • Demian Obregon,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    Search for more papers by this author
  • Terrence Town,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    2. Maxine Dunitz Neurosurgical Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    Search for more papers by this author
  • Jun Tan

    Corresponding author
    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA
    2. Center for Excellence in Aging and Brain Repair, Department of Neurosurgery University of South Florida, Tampa, FL, USA
    Search for more papers by this author

Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 13, Issue 5, 1001, Article first published online: May 2009

*Correspondence to: Dr. Jun TAN, Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 102, Tampa, FL 33612, USA.
Tel.: 813–974-9326; Fax: 813–974-1130
E-mail: jtan@health.usf.edu

Abstract

Glycogen synthase kinase 3 (GSK-3) dysregulation is implicated in the two Alzheimer's disease (AD) pathological hallmarks: β-amyloid plaques and neurofibrillary tangles. GSK-3 inhibitors may abrogate AD pathology by inhibiting amyloidogenic γ-secretase cleavage of amyloid precursor protein (APP). Here, we report that the citrus bioflavonoid luteolin reduces amyloid-β (Aβ) peptide generation in both human ‘Swedish’ mutant APP transgene-bearing neuron-like cells and primary neurons. We also find that luteolin induces changes consistent with GSK-3 inhibition that (i) decrease amyloidogenic γ-secretase APP processing, and (ii) promote presenilin-1 (PS1) carboxyl-terminal fragment (CTF) phosphorylation. Importantly, we find GSK-3α activity is essential for both PS1 CTF phosphorylation and PS1-APP interaction. As validation of these findings in vivo, we find that luteolin, when applied to the Tg2576 mouse model of AD, decreases soluble Aβ levels, reduces GSK-3 activity, and disrupts PS1-APP association. In addition, we find that Tg2576 mice treated with diosmin, a glycoside of a flavonoid structurally similar to luteolin, display significantly reduced Aβ pathology. We suggest that GSK-3 inhibition is a viable therapeutic approach for AD by impacting PS1 phosphorylation-dependent regulation of amyloidogenesis.

Ancillary