Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic

Area of Science:

• Neuroscience
• Molecular Biology
• Alzheimer's Disease Pathogenesis

Background:

• The role of amyloid-beta (Aβ) peptides in Alzheimer's disease (AD) is debated, with questions about whether they are synaptogenic or synaptotoxic.
• Understanding Aβ's dual function is crucial for developing effective AD therapies.

Purpose of the Study:

• To investigate the concentration-dependent and aggregation-dependent effects of synthetic Aβ40, Aβ42, and Aβ42arctic peptides on human neurons.
• To elucidate the dichotomy of Aβ peptides as either synapse-promoting or synapse-damaging.

Main Methods:

• Chronic treatment of human neurons with chemically defined synthetic Aβ peptides (Aβ40, Aβ42, Aβ42arctic) at controlled concentrations.
• Assessment of peptide effects on synapse formation and toxicity, including synaptic vesicle cluster dynamics and synapse loss.

Main Results:

• Free Aβ40 (higher concentrations) and free Aβ42 (lower concentrations) were found to be synaptogenic, promoting synapse formation.
• Aggregated Aβ42 and Aβ42arctic (higher concentrations) exhibited neurotoxicity and synaptotoxicity, leading to synapse loss.
• Inactive sequences confirmed the specificity of Aβ's functional effects.

Conclusions:

• Aβ peptides display an aggregation-dependent functional dichotomy, acting as either synaptogenic or synaptotoxic agents.
• This finding provides insight into the balance between physiological synapse organization and pathological disruption in AD.
• Therapeutic strategies may involve shifting Aβ peptides from aggregated to free states rather than complete suppression.