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

Journal article
Authors S. De
D. R. Whiten
F. S. Ruggeri
C. Hughes
M. Rodrigues
D. I. Sideris
C. G. Taylor
F. A. Aprile
S. Muyldermans
T. P. J. Knowles
M. Vendruscolo
C. Bryant
Kaj Blennow
Ingmar Skoog
Silke Kern
Henrik Zetterberg
D. Klenerman
Published in Acta Neuropathologica Communications
Volume 7
ISSN 2051-5960
Publication year 2019
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Language en
Links dx.doi.org/10.1186/s40478-019-0777-...
Keywords Alzheimer's disease, Mild cognitive impairment, Cerebrospinal fluid, Protein aggregation, Structure-function relation, Super-resolution imaging, Disease mechanism, a-beta oligomer, amyloid-beta, cellular toxicity, ca2+ influx, amyloid-beta(1-42), epitope, dimers, Neurosciences & Neurology
Subject categories Neurosciences

Abstract

Soluble aggregates of amyloid-beta (A beta) 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 A beta 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 100nm, are present in the CSF of AD patients and suggest that different neurotoxic mechanisms are prevalent at different stages of AD.

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