Novel amyloid-beta pathology C. elegans model reveals distinct neurons as seeds of pathogenicity

Abstract

Protein misfolding and aggregation are hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD). In AD, the accumulation and aggregation of tau and the amyloid-beta peptide Aβ_1-42 precedes the onset of AD symptoms. Modelling the aggregation of Aβ is technically very challenging in vivo due to its size of only 42 aa. Here, we employed sub-stoichiometric labelling of Aβ_1-42 in C. elegans to enable tracking of the peptide in vivo, combined with the "native" aggregation of unlabeled Aβ_1-42. Expression of Aβ_1-42 leads to severe physiological defects, neuronal dysfunction and neurodegeneration. Moreover, we can demonstrate spreading of neuronal Aβ to other tissues. Fluorescence lifetime imaging microscopy enabled a quantification of the formation of amyloid fibrils with ageing and revealed a heterogenic yet specific pattern of aggregation. Notably, we found that Aβ aggregation starts in a subset of neurons of the anterior head ganglion, the six IL2 neurons. We further demonstrate that cell-specific, RNAi-mediated depletion of Aβ in these IL2 neurons systemically delays Aβ aggregation and pathology.

Keywords: Aggregation; Amyloid-beta; C. elegans; Fluorescence lifetime imaging (FLIM); Neurodegeneration; Spreading.