INVESTIGATING THE PROTECTIVE EFFECTS OF VITAMIN B12 ON AMYLOID BETA PROTEOTOXICITY IN A C. ELEGANS MODEL OF ALZHEIMER’S DISEASE
Date
2024-05
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University of Delaware
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects
millions of Americans as the leading cause of dementia. Amyloid-beta (Aβ) plaques are one of
the major pathological hallmarks of AD. Utilizing the model organism Caenorhabditis elegans,
we are identifying factors that impact Aβ proteotoxicity in vivo. When toxic human Aβ is
transgenically expressed in the C. elegans body wall muscles, the Aβ accumulates, and the
worms paralyze. Members of the Tanis lab previously discovered that different E. coli diets,
specifically differences in availability of vitamin B12, have a significant effect on the time it
takes Aβ animals to paralyze. Since AD is a neurodegenerative disorder, we transitioned from
working with body wall muscle expression to focusing on pan-neuronal expression of Aβ and
shifted from evaluating paralysis to investigating chemotaxis behavior.
I designed and performed chemotaxis assays with the chemoattractant isoamyl alcohol
(IA) using wild-type control and neuronal Aβ animals fed a diet with or without vitamin B12
supplementation. All worms were attracted to the IA treatment, but to a significantly lesser
extent for neuronal Aβ animals without B12 supplementation. My results suggest that neuronal
Aβ animals display chemotaxis defects compared to control animals, and B12 supplementation
restores their chemotaxis behavior. To investigate if neuronal Aβ and dietary vitamin B12 have
any effect on learning and memory, I conditioned the worms to IA in the absence of food prior to
conducting the chemotaxis assay. The conditioned control worms learned that IA was associated
with starvation and were repelled by the IA compared to the naive worms. The neuronal Aβ
animals exhibited learning deficits compared to control animals in associating the IA with a
negative state of starvation. Interestingly, vitamin B12 supplementation restored the learning and
memory function of neuronal Aβ animals.
To investigate the potential effects of Aβ and vitamin B12 supplementation on sensory
neuron morphology, I performed DiI staining to visualize sensory neurons. My preliminary
results suggest that neuronal Aβ animals have wavier dendrites and release a greater number of
exophers, vesicles released by neurons under proteotoxic stress, compared to control animals.
Vitamin B12 supplementation seemed to straighten dendrites and reduce the number of
exophers. More imaging would need to be conducted to determine if these qualitative neuronal
structural differences are reproducible. In conclusion, determining the mechanisms of the
vitamin B12 protective effect brings us one step closer to understanding the potential of B12 as a
therapy to target the pathogenic features of Alzheimer’s disease and slow its onset or
progression.