Abstract
The pathophysiological role of Aβ(42) oligomers in the onset of Alzheimer's disease (AD) is heavily disputed, pivoting research toward investigating mixed oligomers composed of Aβ(42) and Aβ(40), which is more abundant but less aggregation-prone. This study investigates Aβ(42):Aβ(40) oligomers in different ratios, examining their adverse effects on endothelial cells, neurons, astroglia, and microglia, as well as in a human blood-brain barrier (BBB) model. Combining label-free Raman microscopy with complementary imaging techniques and biochemical assays, we show the prominent impact of Aβ(40) on Aβ(42) fibrillation, suggesting an inhibitory effect on aggregation. Mixed oligomers, especially with low proportions of Aβ(42), were equally detrimental as pure Aβ(42) oligomers regarding cell viability, functionality, and metabolism. They also differentially affected lipid droplet metabolism in BBB-associated microglia, indicating distinct pathophysiological responses. Our findings demonstrate the overarching significance of the Aβ(42):Aβ(40) ratio in Aβ oligomers, challenging the traditional focus on Aβ(42) in AD research.