Quercetin reduces eIF2α phosphorylation by GADD34 induction.

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.