Abstract

Neurodegenerative diseases
predominantly affect older cohorts, but the disease progression occurs from
earlier in adult life. The ability to monitor early mobility decline throughout
adulthood, i.e. prior to the onset of severe symptoms in old age, can inform
the search for preventative interventions and the understanding of disease
onset mechanisms.

There are several C. elegans models of neurodegeneration
but manual assays are subjective, labour intensive and provide binary data at
single time points per animal – namely time of paralysis. Magnitude
Biosciences’ automated imaging system monitors worm movement while
simultaneously revealing in-depth movement data unavailable to manual methods
and is scalable to study hundreds of plates of animals. Additionally, manual
assays disproprotionately use muscle-expressing strains, due to their clear
phenotypic effects on mobility, but neuron-expressing strains are more
physiologically relevant.

Magnitude Biosciences technology
near-continuously monitors up to 90 6 cm petri dishes, with 30 worms per dish,
up to 10 days. Using strains expressing polyglutamine (Huntington’s disease)
and amyloid-beta (Alzheimer disease), we show that these transgenes are
associated with movement decline trackable throughout the life course, in both
muscle and neuron-expressing strains.

Separately, tracking mobility
throughout adulthood allows to detect time-dependent effects of age-related
diseases interventions. By exposing a wild-type C. elegans strain to metformin, rapamycin, alpha-ketoglutarate and
resveratrol, we detected a diversity of mobility effects at either middle or
late adulthood, which is informative not only of mode of action but can inform
age-specific timing for administration to patients. 

Our findings validate Magnitude Biosciences’ C. elegans automated assay
as a robust system to screen mutants and pharmaceutical therapies for
age-rel