Alzheimer's Disease-Associated Proteomic Changes in Olfactory Stem Cells Show Pathway-Level Transcriptomic Overlap
- 1QIMR Berghofer Medical Research Institute
Abstract
Alzheimer's disease (AD) is a progressive, neurodegenerative disorder and the leading cause of dementia worldwide. Although recent therapeutic advances have provided some disease-modifying potential, there is currently no curative treatment for AD, highlighting the need for improved disease models and early biomarkers. Olfactory mucosal stem cells, which can be expanded in vitro as olfactory neurosphere-derived (ONS) cells, represent a promising source for biomarker discovery because olfactory tissue is more accessible than central nervous system tissue and has been reported to exhibit AD-related pathological changes. In this study, we used subcellular fractionation-based proteomics, reconstructed bulk proteomics and integrated transcriptomic-proteomic analyses to characterise alterations in ONS cells derived from healthy control, mild cognitive impairment (MCI) and AD individuals. Fraction-specific proteomics identified cytoplasmic and nuclear-enriched protein abundance changes, including alterations in proteins and pathways associated with cytoskeletal organisation, RNA processing, intracellular trafficking, autophagy and mitochondrial/metabolic processes. Reduced LC3B abundance in cytoplasmic AD ONS cells was supported by western blot analysis, although LC3B abundance alone does not indicate altered autophagic flux. Reconstructed bulk proteomics identified 40 FDR-significant proteins in AD compared with HC, defining an AD-associated protein signature enriched for extracellular matrix, cytoskeletal, organelle-associated and RNA-processing pathways. Despite proteomic enrichment of mitochondrial and metabolic pathways, Seahorse Mito Stress Test analysis did not identify significant group-level differences in mitochondrial respiration. Integrated transcriptomic-proteomic analysis revealed partial RNA-protein concordance and pathway-level overlap across disease-associated processes. Together, these findings support the use of patient-derived ONS cells as a model for investigating AD- and MCI-associated molecular changes and highlight protein signatures for further validation.
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BibTeX
@misc{rantanen2026alzheimers,
title = {{Alzheimer's Disease-Associated Proteomic Changes in Olfactory Stem Cells Show Pathway-Level Transcriptomic Overlap}},
author = {L. M. Rantanen and H. Robinson and D. DutraVoigt and X. Diaz and R. Lampinen and S. Mykkanen and J. Kalapudas and A. M. Koivisto and E. Penttila and L. E. Oikari and H. Quek and K. M. Kanninen and A. R. White},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760270},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760270v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Alzheimer's Disease-Associated Proteomic Changes in Olfactory Stem Cells Show Pathway-Level Transcriptomic Overlap
AU - L. M. Rantanen
AU - H. Robinson
AU - D. DutraVoigt
AU - X. Diaz
AU - R. Lampinen
AU - S. Mykkanen
AU - J. Kalapudas
AU - A. M. Koivisto
AU - E. Penttila
AU - L. E. Oikari
AU - H. Quek
AU - K. M. Kanninen
AU - A. R. White
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760270
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760270v1
AB - Alzheimer's disease (AD) is a progressive, neurodegenerative disorder and the leading cause of dementia worldwide. Although recent therapeutic advances have provided some disease-modifying potential, there is currently no curative treatment for AD, highlighting the need for improved disease models and early biomarkers. Olfactory mucosal stem cells, which can be expanded in vitro as olfactory neurosphere-derived (ONS) cells, represent a promising source for biomarker discovery because olfactory tissue is more accessible than central nervous system tissue and has been reported to exhibit AD-related pathological changes. In this study, we used subcellular fractionation-based proteomics, reconstructed bulk proteomics and integrated transcriptomic-proteomic analyses to characterise alterations in ONS cells derived from healthy control, mild cognitive impairment (MCI) and AD individuals. Fraction-specific proteomics identified cytoplasmic and nuclear-enriched protein abundance changes, including alterations in proteins and pathways associated with cytoskeletal organisation, RNA processing, intracellular trafficking, autophagy and mitochondrial/metabolic processes. Reduced LC3B abundance in cytoplasmic AD ONS cells was supported by western blot analysis, although LC3B abundance alone does not indicate altered autophagic flux. Reconstructed bulk proteomics identified 40 FDR-significant proteins in AD compared with HC, defining an AD-associated protein signature enriched for extracellular matrix, cytoskeletal, organelle-associated and RNA-processing pathways. Despite proteomic enrichment of mitochondrial and metabolic pathways, Seahorse Mito Stress Test analysis did not identify significant group-level differences in mitochondrial respiration. Integrated transcriptomic-proteomic analysis revealed partial RNA-protein concordance and pathway-level overlap across disease-associated processes. Together, these findings support the use of patient-derived ONS cells as a model for investigating AD- and MCI-associated molecular changes and highlight protein signatures for further validation.
ER -