Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Gerontology

Background:

• Alzheimer's Disease (AD) is a leading cause of dementia in older adults.
• Elevated plasma homocysteine (HCy) is a known risk factor and biomarker for AD and other dementias.
• HCy levels are influenced by dietary methionine and vitamin B intake.

Purpose of the Study:

• To investigate the effects of varying homocysteine (HCy) concentrations on neuronal function in mice.
• To examine HCy's impact on oxidative stress, synaptic proteins, and synaptic activity.
• To analyze HCy's in vitro influence on amyloid-beta (Aβ) aggregation kinetics.

Main Methods:

• Experiments were conducted using mice hippocampal slices.
• In vitro studies assessed HCy's effect on Aβ40 aggregation.
• Long-term potentiation was studied under different HCy and Aβ42 conditions.

Main Results:

• Physiological HCy (0.5 µM) increased synaptic proteins; higher doses (30-100 µM) decreased them, increasing oxidative stress and hyperactivity.
• Normal HCy slowed Aβ40 aggregation, while high concentrations accelerated it.
• HCy demonstrated both beneficial and toxic effects on neurons, indicating a hormetic-like response.

Conclusions:

• Homocysteine (HCy) exhibits a dose-dependent, hormetic-like effect on neuronal function and amyloid-beta aggregation.
• HCy's dual action warrants further investigation as a potential therapeutic target and biomarker for dementia.
• Findings support the modifiable risk factor status of HCy in Alzheimer's Disease and other dementias.