Flavonoid‐mediated presenilin‐1 phosphorylation reduces Alzheimer's disease β‐amyloid production
Open Access
- 24 March 2009
- journal article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 13 (3), 574-588
- https://doi.org/10.1111/j.1582-4934.2008.00344.x
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.Keywords
This publication has 66 references indexed in Scilit:
- Fruit and Vegetable Juices and Alzheimer’s Disease: The Kame ProjectThe American Journal of Medicine, 2006
- Luteolin, a flavonoid, inhibits AP-1 activation by basophilsBiochemical and Biophysical Research Communications, 2006
- Formation and Stabilization Model of the 42-mer Aβ Radical: Implications for the Long-Lasting Oxidative Stress in Alzheimer's DiseaseJournal of the American Chemical Society, 2005
- Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's DiseaseJournal of Neuroscience, 2005
- Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in VivoJournal of Biological Chemistry, 2005
- Lithium inhibits Alzheimer's disease‐like tau protein phosphorylation in neuronsFEBS Letters, 1997
- In Vitro Phosphorylation of the Cytoplasmic Domain of the Amyloid Precursor Protein by Glycogen Synthase Kinase‐3βJournal of Neurochemistry, 1996
- The Role of APP Processing and Trafficking Pathways in the Formation of Amyloid β‐ProteinaAnnals of the New York Academy of Sciences, 1996
- Candidate .gamma.-Secretases in the Generation of the Carboxyl Terminus of the Alzheimer's Disease .beta.A4 Amyloid: Possible Involvement of Cathepsin DBiochemistry, 1995
- Glycogen synthase kinase 3β is identical to tau protein kinase I generating several epitopes of paired helical filamentsFEBS Letters, 1993