Neurodegeneration and Disease Modelling Lab

We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions, including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers’ vulnerability to cognitive decline and AD.

Artur Shvetcov, Shannon Thomson, Ann-Na Cho, Heather M Wilkins, Joanne H Reed, Russell H Swerdlow, David A Brown, Alzheimer’s Disease Neuroimaging Initiative, Caitlin A Finney

APOE genotype was the best predictor of dementia cases and healthy controls. Our results, however, demonstrated that there are limitations when using publicly accessible cohort data that may limit the generalizability and interpretability of such predictive models. Future research should examine the use of routine APOE genetic testing for dementia diagnostics. It should also focus on clearly unifying data across clinical cohorts.

Caitlin A Finney, David A Brown, Artur Shvetcov, Alzheimer’s Disease Neuroimaging Initiative, Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing.

Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.

Artur Shvetcov, Shannon Thomson, Jessica Spathos, Ann-Na Cho, Heather M Wilkins, Shea J Andrews, Fabien Delerue, Timothy A Couttas, Jasmeen Kaur Issar, Finula Isik, Simranpreet Kaur, Eleanor Drummond, Carol Dobson-Stone, Shantel L Duffy, Natasha M Rogers, Daniel Catchpoole, Wendy A Gold, Russell H Swerdlow, David A Brown, Caitlin A Finney.

We found that in the frontal cortex, genes involved in mitochondrial energy, ATP, and oxidative phosphorylation, were the most significant dysregulated genes. In the cerebellum, dysregulated genes were involved in mitochondrial cellular biosynthesis (mitochondrial ribosomes). Although there was little overlap between dysregulated genes between the frontal cortex and cerebellum, machine learning models comprised of this overlap. A further functional network analysis of these genes identified that two downregulated genes, ATP5L and ATP5H, which both encode subunits of ATP synthase (mitochondrial complex V) may play a role in AD. Combined, our results suggest that mitochondrial dysfunction, particularly a deficit in energy homeostasis, may play an important role in AD.

Caitlin A Finney, Fabien Delerue, Wendy A Gold, David A Brown, Artur Shvetcov.

Across these pharmacotherapies, we find significant evidence that estrogens indeed offer protection against myriad pathophysiological effects of SCI and lead to improvements in functional outcomes, including locomotion. A STRING functional network analysis of proteins modulated by estrogen after SCI demonstrated that estrogen simultaneously upregulates known neuroprotective pathways, such as HIF-1, and downregulates pro-inflammatory pathways, including IL-17. These findings highlight the strong therapeutic potential of estrogen and estrogenic compounds after SCI.

Artur Shvetcov, Marc J Ruitenberg, Fabien Delerue, Wendy A Gold, David A Brown, Caitlin A Finney.