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Abstract
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.
Highlights
Small soluble aggregates of amyloid-β (Aβ) have been shown to impair hippocampal synaptic plasticity, induce learning deficits and correlate with cognitive impairments both in Alzheimer’s disease (AD) mouse models and humans [13, 27, 30, 40]
Soluble aggregates present in AD and mild cognitive impairment (MCI) cerebrospinal fluid (CSF) induce toxicity by distinct mechanisms We used CSF from individuals diagnosed with MCI, AD as well as healthy controls to perform a series of proof of concept experiments on a small set of clinical samples of CSF to explore if our assays could detect differences between the aggregates present in CSF at different stages of AD
Using this sensitive method capable of detecting entry of a single Ca2+ ion, we found that aliquots of MCI CSF cause greater membrane permeabilisation compared to the AD and control CSF (Fig. 1b)
Summary
Small soluble aggregates of amyloid-β (Aβ) have been shown to impair hippocampal synaptic plasticity, induce learning deficits and correlate with cognitive impairments both in Alzheimer’s disease (AD) mouse models and humans [13, 27, 30, 40]. Most of our current knowledge about the origins and morphologies of the toxic soluble species involved in neurodegenerative mechanisms is derived from in vitro studies and animal models These studies have shown the presence of soluble aggregates with large heterogeneity in size (dimer to higher order multimers), shape (small spherical to fibril like) and structure (random coil to β-sheet) [2, 40]. We used the core AD CSF biomarkers and clinical dementia rating (CDR), which depend on the cognitive ability of individuals (see Methods), to distinguish the MCI cases that had Alzheimer’s pathologic changes These biomarkers used are strongly predictive of the patient having MCI or AD and the agreement is 89–90% [17]. To understand the nature of soluble aggregates present at different stages of AD and how they induce cellular toxicity, we studied CSF samples collected from individuals affected from AD and MCI and compared these with healthy controls
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