Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression.

Soluble aggregates of amyloid-β (Aβ) have been associated with neuronal and synaptic loss in Alzheimer's disease (AD). However, despite significant recent progress, the mechanisms by which these aggregated species contribute to disease progression are not fully determined. As the analysis of human cerebrospinal fluid (CSF) provides an accessible window into the molecular changes associated with the disease progression, we characterised soluble aggregates present in CSF samples from individuals with AD, mild cognitive impairment (MCI) and healthy controls using a range of sensitive biophysical methods. We used super-resolution imaging and atomic force microscopy to characterise the size and structure of the aggregates present in CSF and correlate this with their ability to permeabilise lipid membranes and induce an inflammatory response. We found that these aggregates are extremely heterogeneous and exist in a range of sizes, varying both structurally and in their mechanisms of toxicity during the disease progression. A higher proportion of small aggregates of Aβ that can cause membrane permeabilization are found in MCI CSF; in established AD, a higher proportion of the aggregates were larger and more prone to elicit a pro-inflammatory response in glial cells, while there was no detectable change in aggregate concentration. These results show that large aggregates, some longer than 100 nm, are present in the CSF of AD patients and suggest that different neurotoxic mechanisms are prevalent at different stages of AD.DRW is supported by a Herchel Smith Fellowship. CGT is supported by the European Research Council (669237), KB is supported by the Torsten Söderberg Foundation, Sweden. FAA is supported by a Senior Research Fellowship award from the Alzheimer’s Society, UK. SK was supported by the Swedish state under the agreement between the Swedish Government and the county councils, the ALF-agreement (ALFGBG-813921, ALFGBG-65930, ALF-GBG-716681) and the Swedish Alzheimer Foundation. The Gothenburg H70 Birth Cohort Study was supported by grants from the Swedish Research Council (grants no 2015-02830, 2013-8717), Swedish Research Council for Health, Working Life and Wellfare (grants no 2013-1202, 2013-2300, 2013-2496), Alzheimerfonden, Hjärnfonden and the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (grants no ALF 716681).HZ is a Wallenberg Academy Fellow supported by grants from the Swedish Research Council (grants no 2018-02532), the European Research Council (grants no 681712) and Swedish State Support for Clinical Research (ALFGBG-720931). DK was supported by the Royal Society, the European Research Council with an ERC Advanced Grant (grants no 669237) and ARUK