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).…”

Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders

“…Multiple groups have prepared/enriched primary neuronal cells and stem cells from the OE via nasal biopsy from living subjects [30][31][32][35][36][37][38][39]57,61,62 . Molecular and cellular analyses of these cells from schizophrenia and related disorders have displayed deficits, indicating pathological alternations in the OE in these disorders [30][31][32][35][36][37][38][39]57,61,62 . Although changes associated with the olfactory system in patients with schizophrenia and related disorders are prominent and reproducibly reported from many groups 1,3,7,14,16,18,20,30,35,39,46,[57][58][59][60]63 , their mechanistic link is unclear.…”

“…Several studies have reported a reduced OB volume in these disorders 16,46,[57][58][59][60] , but the sample size of these studies was relatively small. Multiple groups have prepared/enriched primary neuronal cells and stem cells from the OE via nasal biopsy from living subjects [30][31][32][35][36][37][38][39]57,61,62 . Molecular and cellular analyses of these cells from schizophrenia and related disorders have displayed deficits, indicating pathological alternations in the OE in these disorders [30][31][32][35][36][37][38][39]57,61,62 .…”

A review and analysis of key biomarkers in Alzheimer’s disease

“…These features included the thickness of the left paracentral lobule and sulcus (L.PTs), as well as the expression levels of CTCF, UQCR11, and WDR5B genes. Rantanen et al (2022) analyzed transcriptomic data from olfactory neural sphere (ONS)-derived cells in MCI and AD patients. They discovered a significant difference in the expression of AKAP6, which is associated with cognitive function.…”