An Alzheimer’s Disease Patient-Derived Olfactory Stem Cell Model Identifies Gene Expression Changes Associated with Cognition

Abstract

An early symptom of Alzheimer’s disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined.

Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheime’s disease: From early olfactory-related omics signatures to computational repurposing of drug candidates

“…In our case, we used an olfactory proteotranscriptomic-based computational drug-repurposing method to identify drugs that induce a gene expression signature which negatively correlates with early AD phenotype as a strategy for unveiling potential new therapies. First, we compiled the current OT proteomic study as well as other proteomic or transcriptomic studies performed in different primary and secondary olfactory areas (olfactory mucosa, olfactory bulb, entorhinal cortex, hippocampus) in initial stages of AD (11, 14, 22, 33, 34). The OT (Braak I-II) differential dataset was also divided in different lists depending on ALZData parameters (Aβ or Tau correlation in AD murine models, early differentially expressed genes) and on the presence of DEPs in Aβ-plaques, according to previous proteomic evidence obtained by laser-capture microdissection approaches in human AD (30, 31).…”