Biology subjects

Avey, D. R.

Publications and source records attributed to Avey, D. R..

3 recordsLinked to original sources

bioRxiv2024

Spatial Expression of Long Non-Coding RNAs in Human Brains of Alzheimer's Disease

BackgroundLong non-coding RNAs (lncRNAs) are critical regulators of physiological and pathological processes, with their dysregulation increasingly implicated in aging and Alzheimers disease (AD). To investigate the spatial and cellular distribution of lncRNAs in the aging brain, we leveraged published spatial transcriptomics (ST), single-nucleus RNA sequencing (snRNA-seq), and bulk RNA-seq datasets from the dorsolateral prefrontal cortex (DLPFC) of ROSMAP participants with and without pathological AD. ResultsLncRNAs exhibited greater subregion-specific expression than mRNAs, with enrichment in antisense and lincRNA biotypes. Subregion-enriched lncRNAs were generally not cell-type specific, and vice versa. Differential expression analysis of ST data identified AD-associated lncRNAs with distinct spatial patterns and moderate overlap with differentially expressed (DE) lncRNAs from bulk RNA-seq. Gene set enrichment revealed their involvement in chromatin remodeling, epigenetic regulation, and RNA metabolism. We also identified AD DE lncRNAs across major brain cell types using snRNA-seq but overlap with ST DE lncRNAs was limited. Among previously reported lncRNAs, OIP5-AS1 was consistently upregulated in AD in all cortical subregions. Antisense oligonucleotide (ASO) knockdown of OIP5-AS1 in iPSC-derived microglia led to upregulation of pro-inflammatory genes and downregulation of DNA replication and repair pathways. Immunoassays confirmed increased secretion of pro-inflammatory cytokines. The knockdown expression pattern was enriched for microglia-specific AD DE genes and microglia states. ConclusionsThis study provides a spatial and cellular map of lncRNAs in the aging human cortex and identifies subregion-and cell-type-enriched DE lncRNAs in AD. Our findings implicate OIP5-AS1 in microglial activation, suggesting its potential contribution to AD pathogenesis.

neuroscience↗

bioRxiv2024

The YTHDF Proteins Shape the Brain Gene Signatures of Alzheimer's Disease

The gene signatures of Alzheimers Disease (AD) brains reflect an output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulation., yet the dominant factor shaping these signatures remains unclear. To identify the most significant factor that shapes the AD brain signatures, we integrated cellular and molecular features with differential gene expression in in an explainable machine learning framework. Our result indicates that YTHDF proteins, the canonical readers of N6-methyladenosine RNA modification (m6A), are the most influential predictors of the AD brain signatures. We then show that protein modules containing YTHDFs are downregulated in human AD brains, and knocking down and pharmacologically inhibiting YTHDFs in iPSC-derived 2D and 3D neuronal models recapitulate the AD-associated transcriptional signatures. Furthermore, eCLIP-seq analysis revealed that YTHDF proteins influence AD signatures through both m6A-dependent and independent pathways. These results highlight the central role of YTHDF proteins in shaping the gene signatures of AD brains.

neuroscience↗

bioRxiv2024

Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics

Amyloid-beta (A{beta}) plaques and surrounding glial activation are prominent histopathological hallmarks of Alzheimers Disease (AD). However, it is unclear how A{beta} plaques interact with surrounding glial cells in the human brain. Here, we applied spatial transcriptomics (ST) and immunohistochemistry (IHC) for A{beta}, GFAP, and IBA1 to acquire data from 258,987 ST spots within 78 postmortem brain sections of 21 individuals. By coupling ST and adjacent-section IHC, we showed that low A{beta} spots exhibit transcriptomic profiles indicative of greater neuronal loss than high A{beta} spots, and high-glia spots present transcriptomic changes indicative of more significant inflammation and neurodegeneration. Furthermore, we observed that this ST glial response bears signatures of reported mouse gene modules of plaque-induced genes (PIG), oligodendrocyte (OLIG) response, disease-associated microglia (DAM), and disease-associated astrocytes (DAA), as well as different microglia (MG) states identified in human AD brains, indicating that multiple glial cell states arise around plaques and contribute to local immune response. We then validated the observed effects of A{beta} on cell apoptosis and plaque-surrounding glia on inflammation and synaptic loss using IHC. In addition, transcriptomic changes of iPSC-derived microglia-like cells upon short-interval A{beta} treatment mimic the ST glial response and mirror the reported activated MG states. Our results demonstrate an exacerbation of synaptic and neuronal loss in low-A{beta} or high-glia areas, indicating that microglia response to A{beta}-oligomers likely initiates glial activation in plaque-glia niches. Our study lays the groundwork for future pathology genomics studies, opening the door for investigating pathological heterogeneity and causal effects in neurodegenerative diseases.

genomics↗