Post-mortem cortical transcriptomics of Lewy body dementia reveal mitochondrial dysfunction and lack of neuroinflammation

Abstract Objectives Prevalence of Lewy body dementias (LBD) is second only to Alzheimer's disease (AD) among people with neurodegenerative dementia. LBD cause earlier mortality, more intense neuropsychiatric symptoms, more caregivers’ burden, and higher costs than AD. The molecular mechanisms underlying LBD are largely unknown. As advancing molecular level mechanistic understanding is essential for identifying reliable peripheral biomarkers and novel therapeutic targets for LBD, we aimed to identify differentially expressed genes (DEG), and dysfunctional molecular networks in post-mortem LBD brains. Methods We investigated the transcriptomics of post-mortem anterior cingulate and dorsolateral prefrontal cortices of people with pathology-verified LBD using next-generation RNA-sequencing. We verified the identified DEG using high-throughput quantitative polymerase chain reactions. Functional implications of identified DEG, and the consequent metabolic reprogramming were evaluated by Ingenuity pathway analyses, genome-scale metabolic modelling, reporter metabolite analyses, and in-silico gene silencing. Results We identified and verified 12 novel DEGs ( MPO, SELE, CTSG, ALPI, ABCA13, GALNT6, SST, RBM3, CSF3, SLC4A1, OXTR , and RAB44 ) in LBD brains with genome-wide statistical significance. We documented statistically significant downregulation of several cytokine genes. Identified dysfunctional molecular networks highlighted the contributions of mitochondrial dysfunction, oxidative stress, and immunosenescence towards neurodegeneration in LBD. Conclusion Our findings support that chronic microglial activation and neuroinflammation, well-documented in AD, are notably absent in LBD. The lack of neuroinflammation in LBD brains were corroborated by statistically significant downregulation of several inflammatory markers. Identified DEGs, especially downregulated inflammatory markers, may aid distinguishing LBD from AD, and their biomarker potential warrant further investigation.