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THE TRANSCRIPTOMIC LANDSCAPE OF ALZHEIMER'S DISEASE REVEALS DYSREGULATED MITOCHONDRIAL-RELATED PATHWAYS
Abstract
Aims
Mitochondria and mitochondrial-related pathways have become an attractive target for disease-modifying strategies, as mitochondrial dysfunction prior to clinical onset has been widely described in Alzheimer’s Disease (AD) patients and AD animal models. We aim to provide an updated overview of the mechanisms that regulate mitochondrial function and to survey mitochondrial-related pathways in publicly available findings and datasets that study AD among other neurodegenerative diseases.
Methods
Methods: Selected transcriptomic study data was parallelly screened for mitochondrial-related pathways and analyzed for gene-set enrichment considering sex-, cell-, and stage-specific changes in AD.
Results
Mitochondrial- and nuclear-encoded genes of which expression impacts mitochondrial function (e.g. oxidative phosphorylation, autophagy, mitophagy, citric acid cycle) are differentially expressed in AD in a sex-specific manner. In a stage-dependent manner, neuronal cell types are affected earlier than glial cells such as oligodendrocytes and astrocytes in AD. Transcriptomic responses of microglia against amyloid-β or tau protein yields on differential expression patterns of metabolic pathways of interest such as glycolysis, fatty acid oxidation, HIF-1α, and calcium signaling. Amyloid-β induces a transcriptomic signature similar to inflammatory microglia, and tau protein similar to homeostatic microglia.
Conclusions
Several studies have placed mitochondrial dysfunction as a process that contributes to neuronal cell loss, microglial activation and the onset of AD. Whether the dysregulated pathways we observed in AD are not only biomarkers but represent therapeutic targets remains to be investigated. OMICs technologies represent a novel avenue to delineate disease mechanisms not only in AD but in other neurodegenerative diseases.