Exploring the effects of amyloid beta (Aβ⁠) and Tau aggregation on neuronal activity and proteotoxicity in C. elegans

Protein misfolding and aggregation in the human brain are key cellular hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD). At the cellular level, AD is characterised by the formation of extracellular amyloid beta (Aβ⁠) plaques and neurofibrillary tangles (NFTs) of hyperphosphorylated Tau protein, leading to the neuronal degeneration and cognitive decline. Evidence suggests that amyloid formation and structural abnormalities in patients’ brain begin up to 20 years before clinical symptoms appear. My research aimed to correlate the aggregation and off-folding pathway of Aβ⁠1-42 and mutant Tau with the onset of neuronal decline using C. elegans as a model system. First, I developed and characterised a novel C. elegans Tau model pan-neuronally expressing human Tau with the patient-derived mutations P301L and V337M (TauP301L,V337M). I showed that TauP301L,V337M aggregates with the progression of aging and exhibits multiple disease-related phenotypes. To study neuronal activity related to TauP301L,V337M and Aβ⁠1-42 in C. elegans, I used a panneuronal GCaMP6m C. elegans strain. I observed that the decline of neuronal activity precedes the onset of both TauP301L,V337M and Aβ⁠1-42 aggregation, with muscular Aβ⁠1-42 expression exhibiting similarly strong detrimental effect on neuronal activity as Aβ⁠1-42 expression in neurons.

The protein homeostasis (proteostasis) network aims to prevent the toxicity of aberrant proteins through the interplay of molecular chaperones and protein degradation systems. While intracellular chaperones assist in protein folding, refolding of misfolded proteins, preventing aggregation and disaggregating amyloids, little is known about mechanisms contributing to a functional proteome in the extracellular space. Therefore, I investigated the role of the two novel, potential extracellular modifiers (ECMs) - LYS-3 and CLEC-1 - on the aggregation and toxicity of Aβ⁠1-42 using C. elegans as a model system. Knockout of lys-3 and clec-1 decreased Aβ⁠1-42 aggregation in young adult animals, improved development and lifespan and reduced Aβ⁠1-42 spreading to distal tissues. Surprisingly, these findings suggest that LYS-3 and CLEC-1 contribute to Aβ⁠1-42 aggregation and toxicity by promoting amyloid spreading. Further studies are necessary to fully unravel the nature and mechanisms of LYS-3 and CLEC-1 functionality.