AUTHOR=Haessler Annika , Gier Stefanie , Jung Nathalie , Windbergs Maike 

TITLE=The Aβ42:Aβ40 ratio modulates aggregation in beta-amyloid oligomers and drives metabolic changes and cellular dysfunction

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=18

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2024.1516093

DOI=10.3389/fncel.2024.1516093

ISSN=1662-5102

ABSTRACT=<p>The pathophysiological role of Aβ<sub>42</sub> oligomers in the onset of Alzheimer’s disease (AD) is heavily disputed, pivoting research toward investigating mixed oligomers composed of Aβ<sub>42</sub> and Aβ<sub>40</sub>, which is more abundant but less aggregation-prone. This study investigates Aβ<sub>42</sub>:Aβ<sub>40</sub> 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<sub>40</sub> on Aβ<sub>42</sub> fibrillation, suggesting an inhibitory effect on aggregation. Mixed oligomers, especially with low proportions of Aβ<sub>42</sub>, were equally detrimental as pure Aβ<sub>42</sub> 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<sub>42</sub>:Aβ<sub>40</sub> ratio in Aβ oligomers, challenging the traditional focus on Aβ<sub>42</sub> in AD research.</p>