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Investigating the role of Alzheimer's disease-associated presenilin mutations in olfactory deficits Parvand, Mahraz

Abstract

Although olfactory dysfunction is one of the hallmark symptoms in Alzheimer’s disease (AD) prior to the onset of cognitive impairments, little is known about the causes of this dysfunction. The nematode Caenorhabditis elegans is an ideal model for system-level genetic understanding of sensory neural circuits and behavior. Many cases of familial AD are linked to mutations of the presenilin (PS) genes. These genes are homologues with sel-12 genes in C. elegans. The purpose of this project was to examine the association between PS1 and olfactory deficits in order to investigate the cellular mechanism of these dementia-linked deficits. To gain a better understanding of the relationship between presenilin 1 (PS1) mutations in AD and olfactory deficits, chemotaxis experiments (with the attractant diacetyl, and the aversive octanol) were conducted on worms with a mutation in sel-12. I found that adult sel-12 mutant worms had a significantly decreased sensitivity to both odorants compared to wild-type worms. Extrachromosomal array expression of human wild-type PS1 into C. elegans rescued olfactory defects, confirming functional homology between the C. elegans and human gene. However, a PS1 mutant from an Alzheimer’s family was unable to rescue olfactory deficits. Moreover, C. elegans sel-12 mutant worms presented olfactory deficits throughout their lifespan, and the deficit increased with age, similar to the neurodegenerative progression of AD. Based on these data, I concluded that a mutation in the C. elegans homologue of PS1 is associated with decreased olfactory function, and this deficit was rescued by wild-type human PS1 gene. I suggest that altered functioning of the Notch pathway may be involved in these chemosensory deficits. Additionally, to localize the neuron(s) where wild-type sel-12 function is required for normal olfaction, sel-12 and PS1 rescues were conducted in specific sensory neurons, namely the ASH and the AWA neurons responsible for detecting octanol and diacetyl, respectively. Further, an examination of the morphology of the ASH neurons showed increased neurodegeneration over time in sel-12 mutant worms, demonstrating an association with the observed behavioral deficits.

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