Pathogenic Aβ A2V versus protective Aβ A2T mutation: Early stage aggregation and membrane interaction.

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by the aggregation of amyloid-beta (Aβ) peptides.
• Mutations in the amyloid precursor protein (APP) can influence Aβ aggregation and AD pathogenesis.

Purpose of the Study:

• To investigate the impact of specific mutations (A2V and A2T) at position 2 of Aβ1-42 on the early stages of Aβ aggregation and Alzheimer disease pathology.
• To elucidate how these mutations affect the biophysical properties of Aβ peptides and their interaction with model membranes.

Main Methods:

• Static and Dynamic Light Scattering (SLS/DLS) to analyze aggregate size and kinetics.
• Circular Dichroism (CD) spectroscopy to study changes in secondary structure.
• Atomic Force Microscopy (AFM) to visualize fibril morphology.
• X-ray scattering to assess effects on model membranes.
• Cell viability assays using N2a cells.

Main Results:

• The A2V mutation accelerated AD pathology, while the A2T mutation showed a protective effect against disease onset.
• Mutations altered Aβ aggregation pathways, affecting kinetics, aggregate size, and secondary structure evolution, leading to distinct fibril morphologies.
• Mutated peptides exhibited comparable toxicity to N2a cells and induced disordering effects on phospholipid-ganglioside model membranes.

Conclusions:

• Punctual mutations in APP at position 2 of Aβ1-42 significantly influence AD onset and progression through distinct aggregation mechanisms.
• These findings highlight the critical role of specific Aβ residues in modulating aggregation pathways and their pathological consequences.
• The study provides insights into the structural basis of Aβ aggregation and its interaction with cellular membranes, relevant for therapeutic strategies.