Dual GSK3β/SIRT1 modulators for Alzheimer's: mechanisms, drug discovery and future perspectives

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Alzheimer's disease (AD) lacks effective disease-modifying treatments, often due to single-target drug limitations.
• Glycogen synthase kinase-3β (GSK3β) drives tau hyperphosphorylation and amyloid-β (Aβ) production in AD.
• Sirtuin-1 (SIRT1) is a neuroprotective NAD+-dependent deacetylase with potential in AD.

Purpose of the Study:

• To review the rationale for dual inhibition of GSK3β and activation of SIRT1 in Alzheimer's disease.
• To explore natural compounds with dual GSK3β/SIRT1 activity as therapeutic scaffolds.
• To discuss challenges and advances in developing multi-target therapies for AD.

Main Methods:

• Review of mechanistic studies on GSK3β and SIRT1 in AD pathogenesis.
• Analysis of natural compounds (resveratrol, berberine, pterostilbene, quercetin) for dual activity.
• Examination of multi-target drug discovery approaches (hybridization, modeling, nanoformulation).

Main Results:

• Concurrent inhibition of GSK3β and activation of SIRT1 can disrupt AD pathology and enhance neuroprotection.
• Natural compounds demonstrate potential as starting points for dual-action drug design.
• Advances in drug discovery offer strategies to overcome limitations like target selectivity and BBB penetration.

Conclusions:

• A dual GSK3β/SIRT1-targeting strategy represents a systems-level approach to neuroprotection in AD.
• This approach holds promise for developing more effective, disease-modifying therapies for Alzheimer's.
• Overcoming challenges in drug delivery and selectivity is crucial for clinical translation.