Unveiling mitochondria as central components driving cognitive decline in alzheimer's disease through...

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by symptoms such as memory loss and impaired learning. This study conducted a cross-transcriptomic analysis of AD using existing microarray datasets from the hippocampus (HC) and entorhinal cortex (EC), comparing them with age-matched non-AD controls. Both of these brain regions are critical for learning and memory processing and are vulnerable areas that exhibit abnormalities in early AD. The cross-transcriptomic analysis identified 564 significantly differentially expressed genes in HC and 479 in EC. Among these, 151 genes were significantly differentially expressed in both tissues, with functions related to synaptic vesicle clustering, synaptic vesicle exocytosis/endocytosis, mitochondrial ATP synthesis, hydrogen ion transmembrane transport, and structural constituent of cytoskeleton, suggesting a potential association between cognitive decline in AD, synaptic vesicle dynamics, dysregulation of cytoskeleton organization, and mitochondrial dysfunction. Further gene ontology analysis specific to the HC revealed the gene ontology enrichment in aerobic respiration, synaptic vesicle cycle, and oxidative phosphorylation. The enrichment analysis in CA1 of HC revealed differentiation in gene expression related to mitochondrial membrane functions involved in bioenergetics, mitochondrial electron transport, and biological processes associated with microtubule-based process, while analysis in the EC region showed enrichment in synaptic vesicle dynamics which is associated with neurotransmitter release and the regulation of postsynaptic membrane potential and synaptic transmission of GABAergic and glutamatergic synapse. Protein-protein interaction analysis highlighted central hub proteins predominantly expressed in mitochondria, involved in regulation of oxidative stress and ATP synthesis. These hub proteins interact not only within the mitochondria but also with proteins in the vesicular membrane and neuronal cytoskeleton, indicating a central role of mitochondria. This finding underscores the association between clinical symptoms and mitochondrial dysregulation of synaptic vesicle dynamics, cytoskeleton organization, and mitochondrial processes in both the HC and EC of AD. Therefore, targeting these dysregulated pathways could provide promising therapeutic targets aimed at cognitive decline and memory impairment in early AD stages.