Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(2), P. e0293548 - e0293548

Published: Feb. 15, 2024

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the by binding doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction p-ITAM SYK-tSH2 enables phosphorylation. Since reported exacerbate AD pathology, we hypothesized disruption this interaction would beneficial patients. Herein, developed biochemical biophysical assays enable discovery small molecules perturb between SYK-tSH2. We identified distinct chemotypes using high-throughput screen (HTS) orthogonally assessed their binding. Both covalently modify inhibit p-ITAM, however, these compounds lack selectivity limits utility chemical tools.

Language: Английский

---

Molecular hallmarks of excitatory and inhibitory neuronal resilience and resistance to Alzheimer's disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as resilience. Understanding the molecular mechanisms that protect these can identify therapeutic targets for AD dementia. This study aims to define and cellular signatures resilience, protection resistance, by integrating genetics, bulk RNA, single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, control individuals. We analyzed Religious Order Study Rush Memory Aging Project (ROSMAP), including (n=631) multi-regional single nucleus (n=48) sequencing. Subjects were categorized into based on β-amyloid tau status. identified prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, composition distribution. Transcriptomic results, supported GWAS-derived polygenic risk scores, place resilience an intermediate state in continuum. Tissue-level analysis revealed 43 genes enriched nucleic acid metabolism signaling differentially expressed between Only GFAP (upregulated) KLF4 (downregulated) showed differential expression compared controls. Cellular involved reorganization protein folding degradation pathways, with downregulation Hsp90 selective upregulation Hsp40, Hsp70, Hsp110 families excitatory neurons. Excitatory neuronal subpopulations entorhinal cortex (ATP8B1+ MEF2C high ) exhibited unique through neurotrophin (modulated LINGO1) angiopoietin (ANGPT2/TEK) pathways. MEF2C, ATP8B1, RELN key markers resilient populations, characterized vulnerability AD. Protective rare variant enrichment highlighted vulnerable somatostatin (SST) inhibitory interneurons, validated immunofluorescence showing co-expression associated RBFOX1 KIF26B SST+ neurons dorsolateral prefrontal cortex. The maintenance excitatory-inhibitory balance emerges a characteristic hallmarks Resilience include preservation function, excitatory/inhibitory balance, activation protective Specific appear play central role mediating while subset SST interneurons likely provide compensation against AD-associated dysregulation. offers framework leverage natural mitigate neurodegeneration preserve cognition

Language: Английский

---

A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 25, 2025

Abstract The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding observed peripheral changes neurodegeneration. Here, we employ over 909k blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 Parkinson’s (PD), 27 Alzheimer’s (AD), 15 both PD MCI. dataset is interactively accessible a freely available website ( https://www.ccb.uni-saarland.de/adrcsc ). In this work, identify disease-associated cell type composition the sex-specific manner, offering insights into solid tissue AD PD.

Language: Английский

---

Simultaneous analysis of single-cell gene expression and morphology provides new insight into how microglia change with age

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Abstract Cellular morphology is intimately connected with function. While the link between and functional states has been studied extensively, role of subcellular transcript localization in cellular function remains unclear. Here we use microglia, brain’s resident macrophages, as a model to dissect interaction morphology, localization, Using multiplexed error-robust fluorescence situ hybridization combined fluorescent immunohistochemistry, analyzed distribution simultaneously young aged mouse brains. Our approach revealed how mRNA spatial organization varies across microglial states. We identified distinct patterns within processes uncovered morphological heterogeneity transcriptomically defined populations. Notably, found subpopulation disease-associated microglia ramified (displaying numerous processes), challenging conventional assumption Finally, that aging not only alters compartmentalized mRNAs but also reshapes their colocalization networks, shifting functions from synaptic maintenance phagocytic younger brains migration catabolic pathways older findings highlight shaping function, offering new avenues for studying modulating health, disease, aging.

Language: Английский

---

CSF proteomic analysis of semorinemab Ph2 trials in prodromal-to-mild (Tauriel) and mild-to-moderate (Lauriet) Alzheimer`s disease identifies distinct trial cell-type specific proteomic signatures

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 12, 2024

Abstract Targeting of tau pathology has long been proposed as a potential therapeutic strategy for Alzheimer’s disease (AD). Semorinemab is humanized IgG4 monoclonal antibody that binds to all known isoforms full-length with high affinity and specificity. Semorinemab’s safety efficacy have studied in two Phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trials: Tauriel (prodromal-to-mild AD; NCT03289143 ) Lauriet (mild-to-moderate NCT03828747 ). CSF was collected from subset patients at baseline after 49 or 73 weeks 61 Lauriet. We generated large proteomics dataset, using more than 250 cerebrospinal fluid (CSF) samples detecting 3500 proteins, investigate the effects semorinemab each trial. Treatment-induced proteomic signatures were defined study set proteins significantly elevated treatment arm respective study. Integration corresponding gene independent brain single-nucleus RNA-seq datasets AD healthy aged controls revealed signature genes enriched microglial cells, while broadly expressed across major cell types. Furthermore, trial upregulated microglia compared non-demented controls. The elevation such CHI3L1 GPNMB suggested an activated glial state. Taken together, this utilizes dataset assess pharmacodynamic response contributes our understanding how anti-tau influences disease-relevant pathophysiology AD.

Language: Английский

---

Single-cell multi-omics analysis reveals cooperative transcription factors for gene regulation in oligodendrocytes

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 21, 2024

Abstract Oligodendrocytes are the myelinating cells within central nervous system. Many oligodendrocyte genes have been associated with brain disorders. However, how transcription factors (TFs) cooperate for gene regulation in oligodendrocytes remains largely uncharacterized. To address this, we integrated scRNA-seq and scATAC-seq data to identify cooperative TFs that co-regulate target (TG) expression oligodendrocytes. First, identified co- binding TF pairs whose sites overlapped oligodendrocyte-specific regulatory regions. Second, trained a deep learning model predict level of each TG using levels co-binding TFs. Third, models, computed importance TF-TF interaction scores predicting by Shapley scores. We found involving known important differentiation, such as SOX10-TCF12, SOX10-MYRF, SOX10-OLIG2, exhibited significantly higher than others (t-test, p-value < 1e-4). Furthermore, 153 oligodendrocyte-associated eQTLs reside enhancers or promoters where their eGenes (TGs) regulated TFs, suggesting potential novel roles from genetic variants. also experimentally validated some SOX10-OLIG2 SOX10-NKX2.2 co-enrichment analysis, ChIP-seq rat peripheral nerve.

Language: Английский

---

Identification of key lipid metabolism-related genes in Alzheimer’s disease

Lipids in Health and Disease, Journal Year: 2023, Volume and Issue: 22(1)

Published: Sept. 22, 2023

Alzheimer's disease (AD) represents profound degenerative conditions of the brain that cause significant deterioration in memory and cognitive function. Despite extensive research on contribution lipid metabolism to AD progression, precise mechanisms remain incompletely understood. Hence, this study aimed identify key differentially expressed metabolism-related genes (DELMRGs) progression.

Language: Английский

---

(outdated draft) Somatostatin and the pathophysiology of Alzheimer’s disease

Published: April 14, 2024

Since early research on Alzheimer’s disease (AD), it has been known that among the central features of its progression are altered levels neuropeptide somatostatin, and colocalisation somatostatin-positive interneurons (SST-INs) with amyloid-β plaques, leading to cell death. In this theoretical review, I propose a model for pathogenesis AD coheres qualitative profile neuropsychological deficits neurobiological progression. Namely, hypofunctional hyperactive SST-INs struggle control hyperactivity in mid-temporal regions stages, excessive presynaptic GABA-B inhibition, GABA-B1a-APP complex downregulation internalisation, thereby boosting Aβ production. Concomitantly, SST-14 release accumulates near form amyloids, bind toxic mixed oligomers. This leads differential SST-IN death through excitotoxicity, further disinhibition, SST deficits, increased release, fibrillation plaque formation. networks distributions tightly overlap brain. Finally, disinhibition reportedly induces qualitatively agree those found cohorts, pattern separation encoding mnemonic indiscrimination, interference reconsolidation.

Language: Английский

---

The Experts Speak: Challenges in Banking Brain Tissue for Research

Biopreservation and Biobanking, Journal Year: 2024, Volume and Issue: 22(2), P. 179 - 184

Published: April 1, 2024

Language: Английский

---

Phenotype Scoring of Population Scale Single-Cell Data Dissects Alzheimer's Disease Complexity

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 2, 2024

Abstract The complexity of Alzheimer’s disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms (NPSs). However, the etiology these phenotypes remains elusive. To address this, PsychAD project generated a population-level single-nucleus RNA-seq dataset comprising over 6 million nuclei from prefrontal cortex 1,494 individual brains, covering variety AD-related that capture impairment, severity pathological lesions, presence NPSs. Leveraging this dataset, we developed deep learning framework, called Phenotype Associated Single Cell encoder (PASCode), to score single-cell phenotype associations, identified ∼1.5 associate cells (PACs). We compared PACs within 27 distinct brain cell subclasses prioritized subpopulations their expressed genes across various AD upregulation reactive astrocyte subtype with neuroprotective function resilient donors. Additionally, link multiple subpopulation protoplasmic astrocytes alter gene expression regulation donors depression. Uncovering cellular molecular mechanisms underlying has potential provide valuable insights towards identification novel diagnostic markers therapeutic targets. All PACs, along type information, are summarized into an AD-phenotypic atlas for research community.

Language: Английский

---