publications

2025

1. Molecular Neurodegeneration

   

   APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology

   Kristine M. Tran, Nellie E. Kwang, Claire A. Butler, and 22 more authors

   Molecular Neurodegeneration, 2025

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   Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.

2024

1. bioRxiv

   

   Single-nucleus multi-omics identifies shared and distinct pathways in Pick’s and Alzheimer’s disease

   Zechuan Shi, Sudeshna Das, Samuel Morabito, and 12 more authors

   bioRxiv, 2024

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   The study of neurodegenerative diseases, particularly tauopathies like Pick’s disease (PiD) and Alzheimer’s disease (AD), offers insights into the underlying regulatory mechanisms. By investigating epigenomic variations in these conditions, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched non-coding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine-mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database (http://swaruplab.bio.uci.edu/scROAD) to visualize predicted single-cell TF occupancy and regulatory networks.

2. Nat Genet

   

   Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease

   Emily Miyoshi^*, Samuel Morabito^*, Caden M. Henningfield, and 24 more authors

   Nature Genetics, 2024

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   The pathogenesis of Alzheimer’s disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell-cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context.

3. Immunity

   

   Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system

   Vini Tiwari, Bharat Prajapati, Yaw Asare, and 16 more authors

   Immunity, 2024

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   The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.

4. Nat Neurosci

   

   Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice

   Timothy M. O’Shea, Yan Ao, Shinong Wang, and 6 more authors

   Nature Neuroscience, 2024

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   Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes; however, fundamental features of these cells are poorly understood. Here we show that following spinal cord injury or stroke, 90% and 10% of border-forming astrocytes derive, respectively, from proliferating local astrocytes and oligodendrocyte progenitor cells in adult mice of both sexes. Temporal transcriptome analysis, single-nucleus RNA sequencing and immunohistochemistry show that after focal CNS injury, local mature astrocytes dedifferentiate, proliferate and become transcriptionally reprogrammed to permanently altered new states, with persisting downregulation of molecules associated with astrocyte–neuron interactions and upregulation of molecules associated with wound healing, microbial defense and interactions with stromal and immune cells. These wound repair astrocytes share morphologic and transcriptional features with perimeningeal limitans astrocytes and are the predominant source of neuroprotective borders that re-establish CNS integrity around lesions by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.

5. Alzheimer’s & Dementia

   

   BIN1K358R suppresses glial response to plaques in mouse model of Alzheimer’s disease

   Laura Fernandez Garcia‐Agudo, Zechuan Shi, Ian F. Smith, and 24 more authors

   Alzheimer’s & Dementia, 2024

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   The BIN1 coding variant rs138047593 (K358R) is linked to Late‐Onset Alzheimer’s Disease (LOAD) via targeted exome sequencing. To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock‐in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer’s pathology. The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild‐type and 5xFAD backgrounds homozygous for the BIN1K358R variant. The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12‐month‐old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

2023

1. Molecular Neurodegeneration

   

   A Trem2R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

   Kristine M. Tran, Shimako Kawauchi, Enikö A. Kramár, and 26 more authors

   Molecular Neurodegeneration, 2023

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   The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer’s Disease (AD). Unfortunately, many current Trem2 R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products.

2022

1. STAR Protoc

   

   Protocol for single-nucleus ATAC sequencing and bioinformatic analysis in frozen human brain tissue

   Zechuan Shi^*, Sudeshna Das^*, Samuel Morabito, and 2 more authors

   STAR Protocols, 2022

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   Single-nucleus ATAC sequencing (snATAC-seq) employs a hyperactive Tn5 transposase to gain precise information about the cis-regulatory elements in specific cell types. However, the standard protocol of snATAC-seq is not optimized for all tissues, including the brain. Here, we present a modified protocol for single-nuclei isolation from postmortem frozen human brain tissue, followed by snATAC-seq library preparation and sequencing. We also describe an integrated bioinformatics analysis pipeline using an R package (ArchRtoSignac) to robustly analyze snATAC-seq data. For complete details on the use and execution of this protocol, please refer to Morabito et al. (2021).

2018

1. Pedosphere

   

   Elevated CO2 Accelerates Phosphorus Depletion by Common Bean (Phaseolus vulgaris) in Association with Altered Leaf Biochemical Properties

   Zhong Ma, Jennifer Flynn, Grant Libra, and 1 more author

   Pedosphere, 2018

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   Phosphorus (P) is a major limiting factor for plant productivity in many ecosystems and agriculture. The projected increase in atmospheric CO2 is likely to result in changes in plant mineral consumption and growth. We studied P depletion by common bean (Phaseolus vulgaris) cultured hydroponically under ambient (377 ± 77 μmol mol−1) or elevated (650 ± 32 μmol mol−1) CO2 in media of low or high P. Under elevated CO2 compared to ambient CO2, the maximum P depletion rate increased by 98% at low P and 250% at high P, and P was depleted about 2–5 weeks sooner; leaf acid phosphatase (APase) activity and chlorophyll content both increased significantly; root-to-shoot ratio increased significantly at high P, although it was unaffected at low P; lateral root respiration rate showed no change, suggesting that CO2 did not affect P depletion via metabolic changes to the roots; the total biomass at final harvest was significantly higher at both low and high P. Our data showed that the increased rate and amount of P depletion during plant growth under elevated CO2 occurred in association with alterations in leaf biochemical properties, i.e., enhanced activities of leaf APase and increased leaf chlorophyll content.