Postmortem Cortical Transcriptomics of Lewy Body Dementia Reveal Mitochondrial Dysfunction and Lack of Neuroinflammation
Open accessAbstract
Objective 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, the authors aimed to identify differentially expressed genes (DEG), and dysfunctional molecular networks in postmortem LBD brains.Methods The authors investigated the transcriptomics of postmortem anterior cingulate and dorsolateral prefrontal cortices of people with pathology-verified LBD using next-generation RNA-sequencing. The authors 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 modeling, reporter metabolite analyses, and in silico gene silencing.Results The authors 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. The authors documented statistically significant down-regulation of several cytokine genes. Identified dysfunctional molecular networks highlighted the contributions of mitochondrial dysfunction, oxidative stress, and immunosenescence toward 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 was corroborated by statistically significant down-regulation of several inflammatory markers. Identified DEGs, especially down-regulated inflammatory markers, may aid distinguishing LBD from AD, and their biomarker potential warrant further investigation.
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Transcriptomic and protein expression analyses of postmortem brain tissue in DLB did not reveal significant microglial activation.
“Also, transcriptomic and protein expression analyses of postmortem brain tissue in DLB did not reveal significant microglial activation.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [423]
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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- Authors
- Rajkumar, A. P., Bidkhori, G., Shoaie, S., Clarke, E., Morrin, H., Hye, A., Williams, G., Ballard, C., Francis, P., & Aarsland, D.
- Affiliations
- King's College London (GB)
- Guy's Hospital (GB)
- Corresponding author
- Rajkumar, Anto P.
- ORCID
- Venue
- The American Journal of Geriatric Psychiatry
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 28
- Issue
- 1
- Pages
- 75-86
- ISSN
- 1064-7481 (ISSN-L)
- OpenAlex
- W2953974406
- Cited by
- 65
- References
- 50
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 12 · 2023: 16 · 2022: 11 · 2021: 3 · 2020: 6
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- American Journal of Geriatric Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (acceptedVersion, other-oa)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion)
- Funders
- King's College London
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- dementia with Lewy bodies, differentially expressed genes, mitochondrial dysfunction, neuroinflammation, microglial activation, oxidative stress, immunosenescence, metabolic reprogramming, anterior cingulate cortex, dorsolateral prefrontal cortex, Alzheimer's disease differential diagnosis, peripheral biomarkers, gene silencing
- MeSH terms
- Brain, Diagnosis, United Kingdom, Gyrus Cinguli, Humans, Inflammation, Parkinson Disease, Tissue Banks, Down-Regulation, Up-Regulation, Prefrontal Cortex, Sequence Analysis, RNA, Lewy Body Disease, High-Throughput Nucleotide Sequencing, Transcriptome
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