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Panos Roussos

Publications and source records attributed to Panos Roussos.

5 recordsLinked to original sources
PubMed2026

Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains.

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.

alpha-Synuclein↗
PubMed2026

Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.

Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.

Humans↗
PubMed2026

Optimizing Control Definitions in Opioid Use Disorder Genetic Research Using Electronic Health Records.

Amidst the opioid crisis, understanding the genetic basis of opioid use disorder (OUD) is crucial for identifying biological mechanisms and intervention points. However, genome-wide association studies (GWASs) have been hampered by inadequate sample sizes and often the use of control populations not assessed for prior opioid exposure. Because opioid exposure is a prerequisite for the development of OUD, consideration of exposure history in controls is important. Electronic health record data (EHR) paired with genomic information allow a broader sampling of patients with OUD and exposed controls. We leveraged data across two healthcare systems to evaluate the impact of using controls not screened for opioid exposure ('generic') versus minimally opioid-exposed control ('exposed'). First, at the phenotypic level, we conducted phenome-wide association studies (PheWAS) to compare the medical comorbidity profiles of OUD cases when using generic versus exposed controls. While PheWAS results for OUD-related comorbidities were more pronounced when using the generic group, 83% of the disease associations were overlapping and of similar effect sizes. Second, at the genetic level, we conducted GWAS (cases vs. generic; cases vs. exposed) and assessed differences in genetic correlations and degrees of phenotypic misclassification. Genetic results were concordant across control groups based on heritability (generic: 0.16 ± 0.07 vs. 0.10 ± 0.07), associations with the coding OPRM1 variant rs1799971 (pgeneric = 8.83E-03 vs. pexposed = 1.83E-02) and genetic correlations with prior OUD GWAS (rg-generic = 0.83 ± 0.26 vs. rg-exposed = 0.78 ± 0.27). Although GWASs were limited by sample size (Ngeneric = 6269, Nexposed = 6365), compared to an independent OUD GWAS (N = 425 944), the dilution value for the two GWAS was not different from 1, suggesting no major impact of phenotypic misclassification. This study represents the first effort to enhance OUD genetic research through optimization of control definitions using EHR data. Generic controls ascertained within the US health systems, where exposure to prescription opioids is high, offer a practical alternative for genetic studies of OUD.

Humans↗
PubMed2026

Dynamic Alterations in the Blood Transcriptome Characterize Drug Use Behavior and Co-Morbidities in Cocaine Use Disorder: A Preliminary Study.

Individuals with cocaine use disorder (CUD) who attempt abstinence experience craving and relapse that can benefit from multimodal treatment monitoring. Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome are not only limited but also computationally complex. Therefore, we developed an analytical pipeline to investigate the connection between drug use behaviors during abstinence and change in the blood transcriptome. We conducted a longitudinal study with CUD (n = 12 subjects) and collected behavioral metrics and blood RNA-seq at baseline, 3, 6, and 9 months. Our analytical pipeline of the high-dimensional data encompasses hierarchical k-means clustering to classify subjects to responder groups based on behavioral scores and abstinence duration, in silico cell deconvolution, differential analysis with correlated multivariate testing over time, gene set enrichment analysis, and gene co-expression with time splines and RNA-seq data. The pipeline captured dynamic changes in behavioral scores and abstinence duration in responder groups. Genes showing differential transcript-level expression were enriched in substance use and cardiovascular disease-associated genetic risk loci in responder groups. Lastly, time-dependent gene co-expression revealed dynamic changes related to immune processes, cell cycle, RNA-protein synthesis, and second messenger signaling for days of abstinence. This is a preliminary investigation, providing an innovative and scalable pipeline for blood-based longitudinal RNA-seq studies in CUD, potentially applicable to other substance use disorders. It outlines a data-driven approach for analyzing composite longitudinal drug use behavioral phenotypes with blood-based transcriptomics. We also demonstrate changes in drug use behaviors and the blood transcriptome during drug abstinence.

Humans↗
PubMed2024

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer's Disease.

The complex roles of myeloid cells, including microglia and perivascular macrophages, are central to the neurobiology of Alzheimer's disease (AD), yet they remain incompletely understood. Here, we profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 unique donors covering the human lifespan and varying degrees of AD neuropathology. We delineated 13 transcriptionally distinct myeloid subtypes organized into 6 subclasses and identified AD-associated adaptive changes in myeloid cells over aging and disease progression. The GPNMB subtype, linked to phagocytosis, increased significantly with AD burden and correlated with polygenic AD risk scores. By organizing AD-risk genes into a regulatory hierarchy, we identified and validated MITF as an upstream transcriptional activator of GPNMB, critical for maintaining phagocytosis. Through cell-to-cell interaction networks, we prioritized APOE-SORL1 and APOE-TREM2 ligand-receptor pairs, associated with AD progression. In both human and mouse models, TREM2 deficiency disrupted GPNMB expansion and reduced phagocytic function, suggesting that GPNMB's role in neuroprotection was TREM2-dependent. Our findings clarify myeloid subtypes implicated in aging and AD, advancing the mechanistic understanding of their role in AD and aiding therapeutic discovery.

Journal Article↗