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

  1. Kavon Rezai-Zadeh1,
  2. R. Douglas Shytle1,2,
  3. Yun Bai1,
  4. Jun Tian1,
  5. Huayan Hou1,
  6. Takashi Mori1,3,
  7. Jin Zeng1,
  8. Demian Obregon1,
  9. Terrence Town1,4,
  10. Jun Tan1,2,*

Article first published online: 10 APR 2008

DOI: 10.1111/j.1582-4934.2008.00344.x

Issue

Journal of Cellular and Molecular Medicine

Journal of Cellular and Molecular Medicine

Volume 13, Issue 3, pages 574–588, March 2009

Additional Information

How to Cite

Rezai-Zadeh, K., Douglas Shytle, R., Bai, Y., Tian, J., Hou, H., Mori, T., Zeng, J., Obregon, D., Town, T. and Tan, J. (2009), Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease β-amyloid production. Journal of Cellular and Molecular Medicine, 13: 574–588. doi: 10.1111/j.1582-4934.2008.00344.x

Author Information

  1. 1

    Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA

  2. 2

    Center for Excellence in Aging and Brain Repair, Department of Neurosurgery University of South Florida, Tampa, FL, USA

  3. 3

    Institute of Medical Science, Saitama Medical Center/University Kawagoe, Saitama, Japan

  4. 4

    Maxine Dunitz Neurosurgical Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

* *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

Publication History

  1. Issue published online: 24 MAR 2009
  2. Article first published online: 10 APR 2008
  3. Received: February 1, 2008; Accepted: April 5, 2008
Corrected by:

Corrigendum

Vol. 13, Issue 5, 1001, Article first published online: 12 JUN 2009

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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.

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