Biology subjects

Serrano, G. E.

Publications and source records attributed to Serrano, G. E..

At least 19 recordsLinked to original sources

bioRxiv2026

Sex-divergent trajectories of hippocampal and cortical NMDA receptor density across the Alzheimer 's disease continuum

While loss of NMDA receptors (NMDARs) is associated with Alzheimers disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined. We performed quantitative in vitro autoradiography of hippocampus, entorhinal cortex (EC), and parietal cortex using NMDAR and tau radioligands. Relationships between regional NMDAR density and cognitive status assessed by the Mini Mental State Exam (MMSE), and between NMDAR and tau density, were examined by bivariate correlations. In both sexes, the largest AD-related decreases in NMDAR density were observed in the CA1 field. However, there was a significant diagnosis by sex interaction driven by sex-specific changes in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls. Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men. Our data show that changes in hippocampal NMDAR density across the AD continuum are modulated by sex and may contribute to the known sex differences in the clinical trajectory of the disease.

neuroscience↗

bioRxiv2026

APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease

Variation in APOE, notably the {varepsilon}4 allele, profoundly shapes risk and severity of late-onset Alzheimers disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3/3 and APOE4/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain. Graphical Abstract.APOE4/4 in Alzheimers disease reshapes microglial fate along continuous trajectories characterized by proteomic, transcriptional, and epigenetic programs consistent with chronic stress adaptation, alongside distinct composite spatial niches comprised of astrocytic gliosis and cellular senescence. O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/733295v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@b2afa4org.highwire.dtl.DTLVardef@12978f8org.highwire.dtl.DTLVardef@1c4e46dorg.highwire.dtl.DTLVardef@170e44d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Single cell eQTL mapping reveals convergent glial-neuronal risk architecture in Parkinson's disease

Synucleinopathies affect [~]15 million people and are classically divided into neuronal (Parkinsons disease (PD), dementia with Lewy bodies) and glial (multiple system atrophy) disorders. Here we challenge this dichotomy. We functionally fine-map 90 PD GWAS signals across nine cell types in cortex and substantia nigra using disease-context, population-scale single-nucleus eQTL meta-analysis (N = 1,197), bulk brain eQTL analysis (N = 1,182), and Mendelian randomization. A stringent causal framework integrates single-nucleus allelic imbalance (snASE) with orthogonal validation. We identify 125 functional risk genes for 50 loci--nearly doubling supported genes--and assign genes and cell types to over half of GWAS signals. Unexpectedly, 51% of risk genes are regulated in glia, particularly oligodendrocytes and their precursors. Across cell types, risk converges on a shared glial-neuronal vesiculopathy network. These findings uncover a convergent glial-neuronal risk architecture and establish a single-cell atlas for context-aware gene discovery and precision therapeutics for PD.

genetics↗

bioRxiv2026

Increased Binding of Nifene, a PET Imaging Probe for α4β2* Nicotinic Acetylcholinergic Receptors in Hippocampus-Subiculum of Postmortem Human Parkinsons Disease Brain

Non-motor symptoms in Parkinsons disease (PD) may be influenced by the 4{beta}2* subtype of nicotinic acetylcholine receptors (nAChR) present in the hippocampus and subiculum. To continue efforts in PET diagnostics for PD, autoradiographic [18F]nifene binding to 4{beta}2* nAChR was quantitively assessed in the hippocampus-subiculum (HP-SUB) of PD (n = 27; 14 males, 13 females) and cognitively normal (CN) (n = 32; 16 males, 16 females) cases. Anti-ubiquitin for Lewy body and anti--synuclein immunostaining on adjacent slices were analyzed in QuPath and [18F]nifene binding was quantified in OptiQuant. Subiculum had greater [18F]nifene binding (51% to 85%) compared to HP in all subjects. Significantly higher [18F]nifene binding (>250%) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD=3.53 while CN=1.33, a >150% increase in PD. Binding of [18F]nifene to GM and WM individually was >250% greater in PD compared to CN. Male CN exhibited an increase while and male PD exhibited a significant decrease in [18F]nifene binding with aging, while females did not exhibit significant differences. In summary, 4{beta}2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.

neuroscience↗

bioRxiv2026

Separable multidimensional MRI signatures of cellular and structural pathology in Alzheimer's disease

Cognitive decline in Alzheimers disease (AD) reflects progressive disruption of cellular and microstructural organization, yet the biological specificity of MRI signals remains incompletely understood. Multidimensional diffusion-relaxation MRI (MD-MRI) resolves sub-voxel tissue heterogeneity, offering a potential framework to link imaging signals to underlying pathology. We tested the hypothesis that neuronal, glial and white matter pathologies in AD occupy separable regions of diffusion-relaxation space and generate spatially organized imaging signatures linked to cognitive impairment. We integrated ex vivo MD-MRI with co-registered histology from 12 human donors spanning a range of Braak stages and pathological severity. Using nested cross-validated elastic net modeling, we predicted voxelwise A{beta}, pTau, microglia and myelin burden from the multidimensional diffusion-relaxation density distribution. Regional associations were assessed across hippocampal subfields and white matter, and clinical relevance was evaluated by relating MRI-predicted pathology to Mini-Mental State Examination (MMSE) scores. Distinct diffusion-relaxation components were preferentially associated with different pathological markers, indicating separable microstructural signatures. Voxelwise MRI-derived predictions were significantly associated with histological measures of myelin ({rho} = 0.77), pTau ({rho} = 0.62), and microglia ({rho} = 0.61), with weaker correspondence for A{beta} ({rho} = 0.45). Regionally, predicted pathology recapitulated known patterns of selective vulnerability, with elevated pTau and microglial signal in hippocampal subfields and dominant myelin-associated signal in white matter (p < 0.0001). Importantly, higher predicted pTau density in the hippocampus was strongly associated with worse cognitive performance ({rho} = -0.88, p = 0.0014), with a moderate association in white matter ({rho} = -0.66, p = 0.036), suggesting that tau-related microstructural alterations within both gray and white matter contribute to cognitive impairment. By directly linking multidimensional MRI signatures to histologically verified cellular pathology, this study demonstrates that AD-related processes manifest as distinct and spatially organized diffusion-relaxation signatures. These findings provide mechanistic insight into the microstructural basis of MRI contrasts and support the potential of MD-MRI to map regionally specific neuropathological processes in AD. As clinically feasible MD-MRI acquisition protocols continue to emerge, translation of these spectral signatures to in vivo imaging may enable more mechanistically informed assessment of aging and dementia.

neuroscience↗

bioRxiv2026

Aberrant FICD-mediated AMPylation drives α-Synuclein pathology and overall protein dyshomeostasis in dopaminergic neurons in Parkinson's disease

BackgroundFilamentation induced by cAMP domain-containing protein (FICD) is an endoplasmic reticulum (ER)-resident adenylyltransferase that catalyzes protein AMPylation, a post-translational modification. Although FICD-mediated AMPylation has been linked to the fine-tuning of proteostasis and neuronal integrity, its role in neurodegenerative diseases characterized by protein dyshomeostasis remains unclear. Parkinsons disease (PD) is defined by dopaminergic neurodegeneration and aggregation of -synuclein (aSyn) as a consequence of impaired protein homeostasis. We therefore investigated whether dysregulated FICD-mediated AMPylation contributes to PD pathogenesis. MethodsWe combined analyses of human post-mortem PD brain tissue with complementary models, including midbrain dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) of a PD patient carrying an SNCA gene duplication and its isogenic gene dosage-corrected control line, transgenic mouse models of synucleinopathy, and an aSyn-overexpressing H4 neuroglioma cell model. Genetic and pharmacological modulation of FICD activity was integrated with multi-proteomic approaches, including chemical proteomics-based AMPylation profiling, stable isotope labelling with amino acids in cell culture-based global protein turnover analysis, and whole-proteome profiling to identify AMPylation-associated molecular pathways. ResultsFICD was preferentially expressed in dopaminergic neurons and was upregulated in SNCA duplication PD patient-derived neurons, as well as in the basal ganglia of PD post-mortem brains and synucleinopathy mice. Despite this overall increase, the proportion of FICD-expressing dopaminergic neurons was reduced under PD conditions, suggesting selective vulnerability of dopaminergic neurons to FICD. Mechanistically, FICD selectively AMPylated lysosomal proteins, thereby linking AMPylation to the regulation of degradative pathways. Moreover, hyperactivation of FICD-induced AMPylation triggered ER stress, impaired lysosomal function, reduced protein turnover, and ultimately promoted aSyn aggregation and apoptotic cell death. Importantly, pharmacological inhibition of AMPylation reversed aSyn pathology and neurite degeneration in PD patient-derived neurons. ConclusionsWe identify the pathological relevance of FICD-mediated AMPylation in PD-related neurodegeneration and its contribution to aSyn aggregation through a bidirectional interplay with aSyn pathology. Our findings support FICD-mediated AMPylation as a defining molecular switch regulating intracellular protein homeostasis in PD and highlight the FICD-AMPylation pathway as a potential therapeutic target for restoring aSyn pathology and mitigating disease progression.

neuroscience↗

bioRxiv2026

Integrating Long-Read Structural Variant Analysis with single-nucleus RNA-seq to Elucidate Gene Expression Effects in Disease

Structural variants (SVs) are a major source of genetic diversity, yet how they impact cell types in complex brain diseases remains largely unexplored, partially due to limitations of short-read sequencing. Here, we addressed this fundamental question in Parkinsons disease (PD). generating long-read whole-genome sequencing (WGS) data for 100 post-mortem brain samples from a PD cohort, constructing a high-confidence catalog of 74,552 SVs. To resolve their functional impact, we integrated single-nucleus RNA-sequencing data from two brain regions from the same samples and focused functional analyses on SVs proximal to genes previously nominated as cis-regulated, potential causal targets of PD-associated GWAS loci. Using expression quantitative trait locus and allele-specific expression analyses, we uncovered SVs significantly associated with expression in specific cell types as well as effects shared across cell types. This study demonstrates the power of uniting long-read WGS with transcriptomics to uncover SVs underlying complex disease architecture with cell type resolution.

genomics↗

bioRxiv2026

Modeling cis-regulatory variation in human brain enhancers across a large Parkinson's Disease cohort

Genome-wide association studies (GWAS) have linked more than a hundred non-coding genomic loci to Parkinsons disease (PD) risk. Deciphering their functional impact on gene regulation requires cell type-aware modeling approaches to assess the effects of sequence variation on enhancer function and target gene expression. To address this challenge, we generated a comprehensive matched dataset from 190 human donors (115 controls and 75 PD), comprising long-read whole-genome sequencing alongside single nucleus multiome atlases (snATAC-seq and snRNA-seq for 3.1 and 1.1 million nuclei respectively) of the anterior cingulate cortex and substantia nigra. By integrating chromatin accessibility quantitative trait loci (caQTL), DNA methylation QTL (meQTL), and allele-specific chromatin accessibility (ASCA), we identified 53,841 high-confidence cis-acting genetic variants that modulate cell type-specific enhancer accessibility in one or both brain regions. We further demonstrate that sequence-to-function models can accurately predict the impact of these variants directly from the genomic sequence. Novel explainability approaches allowed stratifying these variants according to their regulatory function, with the majority disrupting specific transcription factor binding sites in a cell type specific manner. Integrating these "enhancer variants" (EV) with eQTL mapping and gene locus modeling linked a subset of EVs to their target genes. Finally, we applied these models to prioritize regulatory variants at known PD GWAS loci, bypassing statistical limitations in rare disease-relevant populations like dopaminergic neurons. All together, we establish a unique resource and new sequence modeling strategies to interpret functional non-coding variation in the human brain.

genomics↗

bioRxiv2026

Massive-scale single-nucleus multi-omics identifies novel rare noncoding drivers of Parkinson's disease

Most genetic variants contributing to complex diseases reside in the noncoding genome. While common variants uncovered by genome-wide association studies often fail to explain much of the observed heritability of these diseases, rare variants often have higher effect sizes and cumulatively explain a larger portion of heritability. However, rare variants, particularly rare noncoding variants, have remained under-characterized largely due to the difficulties of accurately predicting variant functionality at scale, given that each individual carries an average of [~]10,000 rare variants. Here, we generated multi-omic data from >3.3 million nuclei sampled from five brain regions across a cohort of 80 individuals with Parkinsons disease (PD) and 21 neurologically normal control individuals with matched 30x whole-genome sequencing. We use this data to identify cell type-specific features of PD, map cell type-specific chromatin accessibility and expression quantitative trait loci, and train machine learning models to predict the effect of variants on gene regulation. We identify rare noncoding variants statistically associated with sporadic PD and extend our approaches to predict drivers of familial PD of unknown genetic origin. Our results underscore the significance of rare noncoding variants in complex diseases and provide a roadmap for applying similar approaches in other disease systems.

genetics↗

bioRxiv2026

Single Plaque Proteomics Reveals the Composition and Dynamics of the Amyloid Microenvironment in Alzheimer's Disease

Alzheimers disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events.

neuroscience↗

bioRxiv2026

Dyrk1a inhibition with the Novel Compound DYR533: A Cross-Disease Therapeutic Strategy Targeting Amyloidosis, Tau Pathogenesis, and Neuroinflammation

Alzheimers disease (AD) and related dementias are rapidly increasing in prevalence, yet disease-modifying therapies remain largely focused on amyloid-{beta} (A{beta}) with limited efficacy against tau pathology and neuroinflammation--key drivers of neurodegeneration and clinical decline. Dual-specificity tyrosine-phosphorylation-regulated kinase 1a (Dyrk1a) phosphorylates tau and amyloid precursor protein and regulates inflammatory signaling, positioning it as a convergence point across pathogenic pathways. We show that brain Dyrk1a protein levels are consistently elevated across ADRDs, replicating findings in AD, confirming prior observations in Picks disease, and demonstrating dysregulation in corticobasal degeneration and progressive supranuclear palsy. We developed DYR533, a selective, orally bioavailable, brain-penetrant Type 1 Dyrk1a kinase inhibitor that also inhibits autophosphorylation and reduces kinase abundance. Across three mouse models (3xTg-AD, PS19, Ts65Dn), DYR533 reduced pathological tau hyperphosphorylation, attenuated neuroinflammation, ameliorated amyloidosis, and improved anxiety-like behavior and spatial memory, collectively supporting Dyrk1a inhibition and DYR533 as a therapeutic strategy for ADRD.

neuroscience↗

bioRxiv2025

Vascular dementia increases levels of methylenetetrahydro-folate reductase and cystathionine β-synthase in female patients and changes gene expression of acetylcholine and glutamate clathrin-sculpted transport vesicles

Vascular dementia (VaD) is a complex clinical syndrome arising from cerebrovascular disease, characterized by cognitive decline and functional impairment, and is projected to double in prevalence over the next three decades. Deficiencies in one-carbon (1C) metabolism are linked to the onset of VaD. Our previous work using mouse models has demonstrated that reduced dietary folic acid intake or genetic disruptions in 1C metabolism exacerbate outcomes in a model of VaD. However, the impact of VaD on one-carbon metabolism remains poorly understood. This study aims to provide a detailed molecular portrait of 1C metabolism within the context of VaD, shedding light on potential molecular mechanisms. In post-mortem medial prefrontal cortex tissue from VaD female and male patients and controls we measured protein expression of the folate receptor (FR) and 1C enzymes including methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), cystathionine {beta}-synthase (CBS) co-localized with NeuN. There was an interaction between VaD and gender for levels of FR. Both male and female VaD had increased levels of ChAT. Female VaD patients had higher levels of MTHFR and CBS when compared to males. VaD is a complex disease; the results of this study demonstrate that VaD impacts neuronal levels of 1C enzymes. Future studies should assess 1C in other cell types of the brain, as well as measure enzyme activity levels.

neuroscience↗

bioRxiv2025

Transcriptomic and protein analysis of human cortex reveals genes and pathways linked to NPTX2 disruption in Alzheimer's disease

BackgroundCognitive resilience to Alzheimers disease (AD) pathology is associated with preserved expression of NPTX2, an activity-regulated synaptic protein involved in circuit plasticity, excitation-inhibition balance, and complement-linked synapse regulation. However, the broader molecular programs coordinated with NPTX2 in resilient individuals remain unclear. MethodsWe analyzed postmortem middle temporal gyrus tissue using targeted PRM-MS proteomics in 135 individuals and bulk RNA-seq in an expanded 575-sample cohort. NPTX2-associated molecular coordination was assessed within cognitively normal low-pathology controls (CN-Lo), cognitively normal high-pathology controls (CN-Hi), mild cognitive impairment (MCI), and AD. Correlation-based approaches were applied using NPTX2 protein and NPTX2 mRNA expression as anchors to define resilience mechanisms in CN-Hi subjects. ResultsNPTX2 protein abundance was preserved across all controls regardless of age and pathology but reduced in MCI and AD. NPTX2 mRNA expression was also invariant across pathology within controls and reduced in MCI and AD but decreased markedly with age. Targeted proteomics identified NPTX2 relationships with synaptic and inhibitory-circuit proteins that were preserved across control groups, alongside CN-Hi-specific recruitment of trafficking, lysosomal, metabolic, and proteostasis-associated proteins. Transcriptome-wide correlations with NPTX2 revealed differences in gene co-expression between groups, identifying a prominent activity-dependent program including BDNF, VGF, SCG2, SST, SERTM1, DUSP4, and EGR4, that was preserved in both CN-Lo and CN-Hi subjects, while genes recruited to the NPTX2 network specifically in CN-Hi implicated immune, neuroprotective, translation, and proteostasis-related pathways. Coupling differential gene expression analysis with co-expression, we further identified five candidate resilience genes whose expression and NPTX correlation was preserved across controls, but lost in MCI and AD: SST, MAL2, TAC1, SERTM1, and RFK. Expression of genes in distinct NPTX2 co-expression classes can be freely explored in our bulk RNA-seq data and other public AD transcriptomic datasets at NeMO Analytics. ConclusionFindings suggest that cognitive resilience in the context of AD neuropathology engages a coordinated molecular state distinct from both persevered cognition without pathology and MCI/AD, which is organized around preserved and selectively remodeled NPTX2-associations. Rather than reflecting broad transcript abundance changes, resilience was characterized by maintained synaptic and inhibitory programs, and adaptive proteostasis and trafficking pathways that distinguish resilient high-pathology individuals from low-pathology controls or symptomatic AD.

bioinformatics↗

bioRxiv2025

Transcriptomic profiling of the middle temporal gyrus reveals differential glial/neuronal dysregulation across Alzheimer disease and aging.

Alzheimers disease (AD), the most common cause of dementia, is characterized by amyloid-{beta} plaques, neurofibrillary tangles, and widespread neuronal dysfunction. Aging, the strongest risk factor for AD, is also associated with some overlapping processes, such as neuronal cell transcriptional downregulation and glial cell activation. The middle temporal gyrus (MTG) is a brain region that supports semantic processing and default-mode connectivity and shows early vulnerability in both aging and AD. Here we profile bulk RNA-seq from 606 postmortem MTG samples with the goal of understanding the transcriptional changes associated with AD and aging. In 217 clinical and neuropathologically confirmed AD versus 290 no-dementia controls donors, we identify 613 differentially expressed genes (390 up, 223 down; |log2 fold change| [≥] 0.5; BH P < 0.05), with NPNT and ADAMTS2 among the top upregulated signals. Cell set enrichment indicates reduced excitatory neuronal signatures together with increased microglial, astrocytic, endothelial, and pericyte programs. Gene-set analyses reveal strong activation of angiogenesis, extracellular-matrix organization, wound response, adaptive immunity, and coordinated suppression of neuronal and mitochondrial processes, including synaptic signaling and respiratory-chain complexes. Multiscale coexpression mapping resolves three disease clusters: a neuron-mitochondrial module suppressed in AD (M5; hub PJA2; key driver GABRB3), a microglial immune module upregulated in AD (M6; hub C1QC; key driver FCER1G), and an increased astrocyte-vascular extracellular-matrix module in AD (M8; hub ESAM; key driver TAGLN). Across 324 non-AD controls aged 24-108 years, aging is associated with declines in gene expression associated with translation, proteostasis, and mitochondrial function and increases in those linked to oligodendrocyte and myelination programs (for example M4; hub CNTN2; key driver MOBP); in a 65+ subset, neuronal and protein-folding modules show the strongest decrements with reduced glial gene expression upregulatio. Our results indicate that late-life aging involves increased glial responses and neuronal/proteostasis suppression, whereas AD is also associated with immune- vascular-ECM activation and suppression of neuronal programs.

genomics↗

bioRxiv2025

Ischemic stroke increases levels of the folate receptor and one-carbon enzymes in male and female brain tissue

Stroke is the second most common cause of death worldwide and predominantly affects individuals over 65 years old. Its prevalence is projected to increase in parallel with the aging global population. Nutrition is a modifiable risk factor for ischemic stroke. Folates, B-vitamins and choline play a central role in one-carbon metabolism (1C), which is a key metabolic network that integrates nutritional signals with biosynthesis, redox homeostasis, epigenetics, regulation of cell proliferation, and stress resistance. Our research group has previously shown that deficiencies in 1C lead to worsened stroke outcomes using preclinical models. However, the impact of ischemic stroke on 1C enzymes in affected brain tissue remains unknown. The objective of this study is to investigate whether ischemic stroke contributes to a change in the levels of 1C enzymes after ischemic stroke in male and female patients. Cortical brain tissue sections from ischemic stroke patients and controls were stained for enzymes involved in 1C. All tissue was co-stained with neuronal nuclei (NeuN) and DAPI (4',6-diamidino-2-phenylindole). The colocalization of all three markers was evaluated by two individuals who were blinded to the experimental groups. Ischemic stroke increased neuronal levels of the folate receptor and 1C enzymes, methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and serine hydroxy methyltransferase (SHMT). In male stroke brain tissue was observed to have increased levels of MTHFR, TS, and SHMT. Female brain tissue had increases in the folate receptor and TS. The results suggest that ischemic stroke leads to increased demand of 1C and that there are some differences between males and females. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/673861v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@18e7c60org.highwire.dtl.DTLVardef@187a339org.highwire.dtl.DTLVardef@1ed0568org.highwire.dtl.DTLVardef@1fdfe31_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation

Proteomic profiling of Alzheimers disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with A{beta} since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates A{beta} assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both A{beta}40 and A{beta}42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of Mdk gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble proteome in these mouse models indicates significant accumulation of A{beta} and A{beta}-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimers disease.

biochemistry↗

bioRxiv2024

Comparative mapping of single-cell transcriptomic landscapes in neurodegenerative diseases

INTRODUCTIONAlzheimers disease (AD), Dementia with Lewy bodies (DLB), and Parkinsons disease (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison of their transcriptomic landscapes. METHODSWe profiled the whole transcriptomes of NDD cortical tissue by snRNA-seq. We used computational analyses to identify common and distinct differentially expressed genes (DEGs), biological pathways, vulnerable and disease-driver cell subtypes, and alteration in cell-to-cell interactions. RESULTSThe same vulnerable inhibitory neuron subtype was depleted in both AD and DLB. Potentially disease-driving neuronal cell subtypes were present in both PD and DLB. Cell-cell communication was predicted to be increased in AD but decreased in DLB and PD. DEGs were most commonly shared across NDDs within inhibitory neuron subtypes. Overall, we observed the greatest transcriptomic divergence between AD and PD, while DLB exhibited an intermediate transcriptomic signature. DISCUSSIONThese results help explain the clinicopathological spectrum of this group of NDDs and provide unique insights into the shared and distinct molecular mechanisms underlying the pathogenesis of NDDs.

neuroscience↗

bioRxiv2024

Experimental and Computational Methods for Allelic Imbalance Analysis from Single-Nucleus RNA-seq Data

Single-cell RNA-seq (scRNA-seq) is emerging as a powerful tool for understanding gene function across diverse cells. Recently, this has included the use of allele-specific expression (ASE) analysis to better understand how variation in the human genome affects RNA expression at the single-cell level. We reasoned that because intronic reads are more prevalent in single-nucleus RNA-Seq (snRNA-Seq), and introns are under lower purifying selection and thus enriched for genetic variants, that snRNA-seq should facilitate single-cell analysis of ASE. Here we demonstrate how experimental and computational choices can improve the results of allelic imbalance analysis. We explore how experimental choices, such as RNA source, read length, sequencing depth, genotyping, etc., impact the power of ASE-based methods. We developed a new suite of computational tools to process and analyze scRNA-seq and snRNA-seq for ASE. As hypothesized, we extracted more ASE information from reads in intronic regions than those in exonic regions and show how read length can be set to increase power. Additionally, hybrid selection improved our power to detect allelic imbalance in genes of interest. We also explored methods to recover allele-specific isoform expression levels from both long- and short-read snRNA-seq. To further investigate ASE in the context of human disease, we applied our methods to a Parkinsons disease cohort of 94 individuals and show that ASE analysis had more power than eQTL analysis to identify significant SNP/gene pairs in our direct comparison of the two methods. Overall, we provide an end-to-end experimental and computational approach for future studies.

genomics↗