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Abstract Title:

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

Abstract Source:

J Cell Mol Med. 2009 Mar;13(3):574-88. Epub 2008 Apr 9. PMID: 18410522

Abstract Author(s):

Kavon Rezai-Zadeh, R Douglas Shytle, Yun Bai, Jun Tian, Huayan Hou, Takashi Mori, Jin Zeng, Demian Obregon, Terrence Town, Jun Tan

Abstract:

Glycogen synthase kinase 3 (GSK-3) dysregulation is implicated in the two Alzheimer's disease (AD) pathological hallmarks: beta-amyloid plaques and neurofibrillary tangles. GSK-3 inhibitors may abrogate AD pathology by inhibiting amyloidogenic gamma-secretase cleavage of amyloid precursor protein (APP). Here, we report that the citrus bioflavonoid luteolin reduces amyloid-beta (Abeta) 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 gamma-secretase APP processing, and (ii) promote presenilin-1 (PS1) carboxyl-terminal fragment (CTF) phosphorylation. Importantly, we find GSK-3alpha 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 Abeta 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 Abeta pathology. We suggest that GSK-3 inhibition is a viable therapeutic approach for AD by impacting PS1 phosphorylation-dependent regulation of amyloidogenesis.

Study Type : Animal Study

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Sayer Ji
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