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

• Published in: Journal of cellular and molecular medicine 2009-03, Vol.13 (3), p.574-588
• Main Authors: Rezai‐Zadeh, Kavon, Douglas Shytle, R., Bai, Yun, Tian, Jun, Hou, Huayan, Mori, Takashi, Zeng, Jin, Obregon, Demian, Town, Terrence, Tan, Jun
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alzheimer Disease - enzymology; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - biosynthesis; Amyloid precursor protein; Amyloidogenesis; Animals; Antibodies; Brain - drug effects; Brain - enzymology; Brain - pathology; Cell Line; Cloning; Cold; Diosmin - administration & dosage; Diosmin - chemistry; Diosmin - pharmacology; Enzyme Activation - drug effects; Flavonoids; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta; Humans; Kinases; Luteolin - chemistry; Luteolin - pharmacology; Mice; Mice, Transgenic; Neurodegenerative diseases; Neurofibrillary tangles; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Pathology; Peptides; Phosphorylation; Phosphorylation - drug effects; Presenilin 1; Presenilin-1 - metabolism; Protein Binding - drug effects; Protein Processing, Post-Translational - drug effects; Proteins; Secretase; Senile plaques; Transgenes; β-Amyloid
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2008.00344.x

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.