Biology subjects

Talanian, R. V.

Publications and source records attributed to Talanian, R. V..

3 recordsLinked to original sources

bioRxiv2023

Distinct Transcriptomic Responses to A beta plaques, Neurofibrillary Tangles, and APOE in Alzheimer's Disease

INTRODUCTIONOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimers disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear. METHODSWe performed laser capture microdissection of A{beta} plaques, the 50m halo around them, tangles with the 50m halo around them, and areas distant (>50m) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTSA{beta} plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. A{beta} plaques had more differentially expressed genes than tangles. We identified a gradient A{beta} plaque>peri-plaque>tangle>distant for these changes. AD APOE{varepsilon}4 homozygotes had greater changes than APOE{varepsilon}3 across locations, especially within A{beta} plaques. DISCUSSIONTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with A{beta} plaques, and are exacerbated by the APOE{varepsilon}4 allele.

neuroscience↗

bioRxiv2023

Endothelial Cells are Heterogeneous in Different Brain Regions and are Dramatically Altered in Alzheimer's Disease

Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimers disease (AD) is obscured by limited understanding of the cellular heterogeneity in normal aged brain and in disease. To address this, we performed single nucleus RNAseq on tissue from 32 AD and non-AD donors each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex and primary visual cortex. Analysis of 51,586 endothelial cells revealed unique gene expression patterns across the five regions in non-AD donors. Alzheimers brain endothelial cells were characterized by upregulated protein folding genes and distinct transcriptomic differences in response to amyloid beta plaques and cerebral amyloid angiopathy (CAA). This dataset demonstrates previously unrecognized regional heterogeneity in the endothelial cell transcriptome in both aged non-AD and AD brain. Significance StatementIn this work, we show that vascular endothelial cells collected from five different brain regions display surprising variability in gene expression. In the presence of Alzheimers disease pathology, endothelial cell gene expression is dramatically altered with clear differences in regional and temporal changes. These findings help explain why certain brain regions appear to differ in susceptibility to disease-related vascular remodeling events that may impact blood flow.

neuroscience↗

bioRxiv2022

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer's disease

Astrocytes play a critical role in brain homeostasis and normal functions but their changes along the spatiotemporal progression of Alzheimers disease (AD) neuropathology remain largely unknown. Here we performed single-nucleus RNA-sequencing on brain regions along the stereotypical progression of AD pathology from donors ranging the entire normal aging-AD continuum comprising 628,943 astrocyte nuclei from 32 donors across 5 brain regions. We discovered temporal gene-expression-trajectories with gene sets differentially activated at various disease stages. Surprisingly, a gene set enriched in proteostasis and energy metabolism, was upregulated in late-stage but unexpectedly returned to baseline levels in end-stage, suggesting exhaustion of response in "burnt-out" astrocytes. The spatial gene-expression-trajectories revealed that astrocytic genes of tripartite synapses are dysregulated in parallel to the stereotypical progression of tangle pathology across regions. We identified astrocyte heterogeneity across brain regions with a continuum from homeostatic to reactive cells through "intermediate" transitional states. These findings suggest complex astrocytic dysfunction in AD neurodegeneration.

neuroscience↗