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Quercetin reduces eIF2α phosphorylation by GADD34 induction.

Miki Hayakawa1, Masanori Itoh1, Kazunori Ohta1

  • 1Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.

Neurobiology of Aging
|June 14, 2015
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Quercetin, a flavonoid, may improve memory in Alzheimer

Keywords:
ATF4Alzheimer's diseaseAmyloid-βGADD34Quercetin

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Alzheimer's disease (AD) pathogenesis involves amyloid β (Aβ) production via γ-secretase.
  • Autophagy impairment and ER stress elevate presenilin 1 and γ-secretase activity through eIF2α phosphorylation and ATF4 translation.
  • Inhibitory molecules for γ-secretase remain largely unknown.

Purpose of the Study:

  • To investigate the role of ATF4 in AD pathogenesis.
  • To identify potential therapeutic compounds targeting γ-secretase activity.
  • To evaluate the effect of quercetin on AD model mice.

Main Methods:

  • Assessed ATF4 expression in APP23 AD model mice and APP23 mice crossed with db/db mice.
  • Investigated quercetin's effect on presenilin 1 expression and Aβ secretion in autophagy-impaired cells.
  • Examined GADD34 induction and eIF2α dephosphorylation in response to quercetin.
  • Evaluated memory function in APP23 mice after long-term quercetin administration.

Main Results:

  • ATF4 expression was increased in APP23 mice brains, further elevated in APP23/db/db mice.
  • Quercetin suppressed presenilin 1 and Aβ secretion by inducing GADD34, leading to eIF2α dephosphorylation and reduced ATF4.
  • GADD34 induction by quercetin was observed in wild-type and APP23 mouse brains.
  • Long-term quercetin feeding delayed memory decline in APP23 mice.

Conclusions:

  • Quercetin may reduce eIF2α phosphorylation and ATF4 expression via GADD34 induction in the brain.
  • Quercetin shows potential for improving memory in aged mice and delaying cognitive decline in early-stage AD.