Resveratrol differentially affects MMP-9 release from neurons and glia; implications for therapeutic efficacy

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Resveratrol, a polyphenol activating sirtuin 1 (SIRT1), modulates matrix metalloproteinase-9 (MMP-9) levels in Alzheimer's dementia (AD) patients' cerebrospinal fluid (CSF).
• MMP-9's function is context-dependent; microglial/pericyte release can damage the blood-brain barrier, while neuronal release promotes synaptic plasticity.
• APOE4 allele is linked to increased glial inflammation in AD.

Purpose of the Study:

• To investigate if resveratrol reduces overall MMP-9 levels in CSF of APOE4 AD patients.
• To determine if resveratrol inhibits inflammation-associated MMP release from glia but spares neuronal MMP release.

Main Methods:

• Analysis of MMP-2, MMP-9, and tissue inhibitor of metalloproteinases-1 (TIMP-1) in CSF from AD patients.
• In vitro studies using cultured microglia, astrocytes, and cortical neurons treated with resveratrol.
• Assessment of basal and lipopolysaccharide (LPS)-stimulated release of MMPs and TIMP-1.

Main Results:

• Resveratrol decreased overall MMP-2 and MMP-9 levels in AD patient CSF.
• Resveratrol reduced CSF TIMP-1 levels in individuals homozygous for APOE4.
• In vitro, resveratrol reduced basal and LPS-stimulated MMP and TIMP-1 release from microglia and astrocytes, but not MMP-9 release from cortical neurons.
• Resveratrol reduced neurocan and brevican release from both neurons and glia.

Conclusions:

• Resveratrol appears to reduce detrimental MMP and TIMP-1 release from activated glia in AD.
• Neuroplasticity-promoting MMP release from neurons is not inhibited by resveratrol.
• Resveratrol's differential effects on glial vs. neuronal MMP release suggest potential therapeutic applications for AD, particularly concerning blood-brain barrier integrity.