Subtype-Selective Neuronal Vulnerability and Compensatory Neuroglial Remodeling in Human Cortical Dementia

Whether the nodal vulnerability in dementia is solely represented by changes in cellular abundance or attrition of cellular transcriptomic landscape attribute to that transition in aging brain is yet to uncover with minutiae. To understand this complication, we have analyzed two snRNA-seq data specific to (I) dorsolateral prefrontal cortex (DLPFC): A comprehensive study of cellular profiling among cognitively normal and pathological ageing and dementia (AD) brain, (II) occipital cortex (OC) in the context of Nasu-Hakola disease along with a tissue level bulk RNA-seq data corresponds to temporal cortex. We pinpoint cellular subpopulations their proportional changes within the nodal points and their transcriptomic profiling. In DLPFC we observed alteration of mitochondrial and synaptic maintenance program in the pathological manifestation of disease. In OC we noticed depleted upper layer CUX2 neuron, PVALB and SST neurons on the contrary an enrichment of RORB and LAMP5 neurons with compromised metabolic states in the disease context. Glial populations are marked by representation of fibrous astrocyte, neuronal-supporting subpopulations associated with extracellular matrix remodeling programs. Proportional increment of intermediate myelinating oligodendrocyte and a decrease in mature myelinating subpopulation highlighted a compromised myelin repair attempt. In temporal cortex at tissue level we observed transcriptomic landscape adopted a neuroglial phenotypes in dementia brain. Cell-Chat analysis demonstrated a shift in cellular coordination towards glial population from neuron in NHD brain. A single cell-based drug reprofiling approach identified efatutazone and balaglitazone as broad-spectrum candidates for major cell types in occipital cortex, whereas major actionable biological targets belong to CDK subtypes and proteasome subunits. Overall, our findings imply cellular persistence do not necessarily substantiate molecular preservation, also the coexistence of cellular vulnerability alongside selective remodeling features, present a cellular framework on how to cope up with degenerative changes.