Exploring the σ2R/TMEM97 protein‐mediated neuroprotective pathway in a C. elegans Alzheimer’s Disease Model of Neurodegeneration

Alzheimer’s disease (AD) is one of the leading causes of death in the aging population around the world. Two genetic risk factors highly correlate with and synergize in the development of AD: mutations altering copy number or processing of the amyloid precursor protein (APP) and the apolipoprotein E4 (APOE4) allelic variant. Using the genetically malleable nematode, C. elegans, we generated a strain expressing a single‐copy human APP and multiple copies of human APOE4, from which we saw progressive neurodegeneration in adulthood. We previously found that small molecule ligands of the sigma 2 receptor/transmembrane protein 97 (σ2R/TMEM97) are neuroprotective in our worm hAPP model of AD and reduce cognitive deficits in a transgenic APP mouse model. Our results suggest that a null allele of the TMEM97 gene ortholog in worm, Y38H6C.16, confers neuroprotection in our new hAPP/hAPOE4 worm model. Using this neurodegeneration model, we have also begun to screen compounds in our norbenzomorphan σ2R/TMEM97 ligand collection for the ability to influence neurodegeneration. Thus far, our findings indicate that σ2R/TMEM97 ligands can promote or inhibit neurodegeneration. To begin to understand the function of σ2R/TMEM97, we generated translational and transcriptional reporters for C. elegans. Elucidating the mechanisms underlying how σ2R/TMEM97 ligands protect against degeneration in our models is imperative in the development of treatments for uncurable neurodegenerative diseases like AD.