Biology subjects

Anand, C.

Publications and source records attributed to Anand, C..

3 recordsLinked to original sources

bioRxiv2025

Distinguish risk genes functioning at presynaptic or postsynaptic regions and key connectomes associated with pathological α-synuclein spreading

Previous studies have suggested that pathological -synuclein (-Syn) mainly transmits along the neuronal network, but several key questions remain unanswered: (1) How many and which connections in the connectome are necessary for predicting the progression of pathological -Syn? (2) How to identify risk gene that affects pathology spreading functioning at presynaptic or postsynaptic regions, and are these genes enriched in different cell types? Here, we addressed these key questions with novel mathematical models. Strikingly, the spreading of pathological -Syn is predominantly determined by the key subnetworks composed of only 2% of the strongest connections in the connectome. We further explored the genes that are responsible for the selective vulnerability of different brain regions to transmission to distinguish the genes that play roles in presynaptic from those in postsynaptic regions. Those risk genes were significantly enriched in microglial cells of presynaptic regions and neurons of postsynaptic regions. Gene regulatory network analyses were then conducted to identify key drivers of genes responsible for selective vulnerability and overlapping with Parkinsons disease risk genes. By identifying and discriminating between key gene mediators of transmission operating at presynaptic and postsynaptic regions, our study has demonstrated for the first time that these are functionally distinct processes.

neuroscience↗

bioRxiv2024

Selective vulnerability and resilience to Alzheimer's disease tauopathy as a function of genes and the connectome

Brain regions in Alzheimers (AD) exhibit distinct vulnerability to the diseases hallmark pathology, with the entorhinal cortex and hippocampus succumbing early to tau tangles while others like primary sensory cortices remain resilient. The quest to understand how local/regional genetic factors, pathogenesis, and network-mediated spread of pathology together govern this selective vulnerability (SV) or resilience (SR) is ongoing. Although many risk genes in AD are known from gene association and transgenic studies, it is still not known whether and how their baseline expression signatures confer SV or SR to brain structures. Prior analyses have yielded conflicting results, pointing to a disconnect between the location of genetic risk factors and downstream tau pathology. We hypothesize that a full accounting of genes role in mediating SV/SR would require the modeling of network-based vulnerability, whereby tau misfolds, aggregates, and propagates along fiber projections. We therefore employed an extended network diffusion model (eNDM) and tested it on tau pathology PET data from 196 AD patients from the Alzheimers Disease Neuroimaging Initiative (ADNI). Thus the fitted eNDM model becomes a reference process from which to assess the role of innate genetic factors. Using the residual (observed - model-predicted) tau as a novel target outcome, we obtained its association with 100 top AD risk-genes, whose baseline spatial transcriptional profiles were obtained from the Allen Human Brain Atlas (AHBA). We found that while many risk genes at baseline showed a strong association with regional tau, many more showed a stronger association with residual tau. This suggests that both direct vulnerability, related to the network, as well as network-independent vulnerability, are conferred by risk genes. We then classified risk genes into four classes: network-related SV (SV-NR), network-independent SV (SV-NI), network-related SR (SR-NR), and network-independent SR (SR-NI). Each class has a distinct spatial signature and associated vulnerability to tau. Remarkably, we found from gene-ontology analyses, that genes in these classes were enriched in distinct functional processes and encompassed different functional networks. These findings offer new insights into the factors governing innate vulnerability or resilience in AD pathophysiology and may prove helpful in identifying potential intervention targets.

neuroscience↗

bioRxiv2023

A meta-analysis of mouse models of tauopathy reveals the cellular underpinnings of selective regional vulnerability

Neurodegenerative diseases such as Alzheimers disease (AD) exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion, but the cellular and molecular underpinnings of regional vulnerability are currently poorly understood. Recent work has identified certain subpopulations of neurons in a few focal regions of interest, such as the entorhinal cortex, that are selectively vulnerable to tau pathology in AD. However, the cellular underpinnings of regional susceptibility to tau pathology are currently unknown, primarily because whole-brain maps of a comprehensive collection of cell types have been inaccessible. Here, we deployed a recent cell-type mapping pipeline, Matrix Inversion and Subset Selection (MISS), to determine the brain-wide distributions of pan-hippocampal and neocortical neuronal and non-neuronal cells in the mouse using recently available single-cell RNA sequencing (scRNAseq) data. We then performed a robust set of analyses to identify general principles of cell-type-based selective vulnerability using these cell-type distributions, utilizing 5 transgenic mouse studies that quantified regional tau in 12 distinct PS19 mouse models. Using our approach, which constitutes the broadest exploration of whole-brain selective vulnerability to date, we were able to discover cell types and cell-type classes that conferred vulnerability and resilience to tau pathology. Hippocampal glutamatergic neurons as a whole were strongly positively associated with regional tau deposition, suggesting vulnerability, while cortical glutamatergic and GABAergic neurons were negatively associated. Among glia, we identified oligodendrocytes as the single-most strongly negatively associated cell type, whereas microglia were consistently positively correlated. Strikingly, we found that there was no association between the gene expression relationships between cell types and their vulnerability or resilience to tau pathology. When we looked at the explanatory power of cell types versus GWAS-identified AD risk genes, cell type distributions were consistently more predictive of end-timepoint tau pathology than regional gene expression. To understand the functional enrichment patterns of the genes that were markers of the identified vulnerable or resilient cell types, we performed gene ontology analysis. We found that the genes that are directly correlated to tau pathology are functionally distinct from those that constitutively embody the vulnerable cells. In short, we have demonstrated that regional cell-type composition is a compelling explanation for the selective vulnerability observed in tauopathic diseases at a whole-brain level and is distinct from that conferred by risk genes. These findings may have implications in identifying cell-type-based therapeutic targets.

neuroscience↗