A5052072340- Neuroinflammation and Neurodegeneration Mechanisms
- Single-cell and spatial transcriptomics
- Alzheimer's disease research and treatments
- MicroRNA in disease regulation
- Bioinformatics and Genomic Networks
- Parkinson's Disease Mechanisms and Treatments
- Nuclear Receptors and Signaling
- Barrier Structure and Function Studies
- RNA regulation and disease
- Neurogenesis and neuroplasticity mechanisms
- Epigenetics and DNA Methylation
- Intracerebral and Subarachnoid Hemorrhage Research
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Advanced biosensing and bioanalysis techniques
- Cell Adhesion Molecules Research
- Reproductive System and Pregnancy
- Computational Drug Discovery Methods
- Genetics and Neurodevelopmental Disorders
- Neurological Disease Mechanisms and Treatments
- Zebrafish Biomedical Research Applications
- Dementia and Cognitive Impairment Research
- Diabetes and associated disorders
- Resilience and Mental Health
- Proteoglycans and glycosaminoglycans research
Mayo Clinic in Florida
2019-2025
Jacksonville College
2021-2025
WinnMed
2019-2024
Abstract To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing 24 disease and control brains focused on vascular astrocyte clusters as main cell types of gliovascular-unit. The majority the transcriptional were pericytes. Of targets predicted to interact with astrocytic ligands, SMAD3 , upregulated pericytes, has highest number ligands including VEGFA downregulated astrocytes. We validated these findings...
Blood-brain barrier (BBB) dysfunction is a key feature of Alzheimer's disease (AD), particularly in individuals carrying the APOE-E4 allele. This worsens neuroinflammation and hinders removal toxic proteins, such as amyloid-beta (Aβ42), from brain. In post-mortem brain tissues animal models, we previously reported that fibronectin accumulates at BBB predominantly carriers. Furthermore, found loss-of-function variant 1 (FN1) gene significantly reduces aggregated levels decreases AD risk among...
Neurogenesis, crucial for brain resilience, is reduced in Alzheimer's disease (AD) that induces astroglial reactivity at the expense of pro-neurogenic potential, and restoring neurogenesis could counteract neurodegenerative pathology. However, molecular mechanisms promoting fate despite AD pathology are unknown. In this study, we used APP/PS1dE9 mouse model induced Nerve growth factor receptor (Ngfr) expression hippocampus. Ngfr, which promotes neurogenic astroglia during amyloid...
Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes human PSP brains, although their cell-specificity unknown. Further, systematic data integration experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets are currently lacking. In this study, we combine bulk tissue (n = 408) single nucleus RNAseq 34)...
Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer's disease (AD), however, neither nor brain region specificity these transcriptome alterations has explored. Using RNA-Seq data from 231 temporal cortex 224 cerebellum samples patients with AD progressive supranuclear palsy (PSP), a tauopathy, we striking correlation the directionality magnitude gene expression changes between 2 neurodegenerative proteinopathies. Further, transcriptomic PSP...
Abstract Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOE ε4 allele male sex have previously been reported associate with increased CAA AD. To inform biomarker therapeutic target discovery, we aimed identify additional genetic risk factors biological pathways involved this vascular component of AD etiology. We present genome-wide association study pathology cases report sex-...
Alzheimer's disease (AD) remains a complex challenge characterized by cognitive decline and memory loss. Genetic variations have emerged as crucial players in the etiology of AD, enabling hope for better understanding mechanisms; yet specific mechanism action those genetic variants remain uncertain. Animal models with reminiscent pathology could uncover previously uncharacterized roles these genes. Using CRISPR/Cas9 gene editing, we generated knockout model abca7, orthologous to human ABCA7...
Abstract Blood-brain barrier (BBB) dysfunction is well-known in Alzheimer’s disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand transcriptional brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue 24 AD and control brains resulting 79,751 nuclei, 4,604 which formed three distinct clusters characterized as activated pericytes, endothelia resting pericytes. We identified differentially...
Abstract Neurogenesis relates to the brain resilience and is reduced in Alzheimer’s disease (AD). Restoring healthy levels of neurogenesis could have beneficial effects for coping with neurodegeneration. However, molecular mechanisms that enhance from astroglial progenitors AD pathology are largely unknown. We used lentiviruses express Ngfr hippocampus APP/PS1dE9 mouse model AD, histologically analyzed changes proliferation neural stem cells neurogenesis; performed single-cell...
Abstract Background Alzheimer’s disease (AD) is neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often quantified Thal phase Braak stage, respectively. Aβ also frequently deposits in the cerebrovasculature with severity categorized a cerebral amyloid angiopathy (CAA) score. These related measures show high variability within AD suggesting distinct underlying mechanisms. We hypothesize that, brain, neuropathology levels of core AD‐related proteins...
Abstract Background A complex, multicellular disease with genetic and immunological elements, Alzheimer’s (AD) affects millions worldwide. There has been previous research linking AD to the missense variants ABI3‐rs616338‐T PLCG2‐rs72824905‐G, altered expression of these genes shown disrupt microglial function. In our understanding risk resilience, limited conducted on how affect subtypes states in AD. Methods We previously identified DOCK8 protein as a target for fluorescent activated...
Abstract Background Progressive supranuclear palsy (PSP) is a devastating primary tauopathy with rapid progression to death. Although several therapies currently in the development pipeline show promising safety profiles and robust target engagement, few demonstrated significant efficacy patients, underscoring need interrogate additional targets novel therapeutic modalities expand potential arsenal. To diversify avenues for PSP related tauopathies (e.g. Alzheimer’s disease), we...
Abstract Background Genetic variations have emerged as crucial players in the etiology of Alzheimer’s disease (AD), and they serve for a better understanding mechanisms; yet specific roles these genetic variants remain uncertain. Animal models with reminiscent pathology could uncover previously uncharacterized genes. Therefore, we generated zebrafish AD to analyze depth molecular biological functions variants. Method Using CRISPR/Cas9, knockout model abca7 , orthologous human ABCA7 . We...
Bulk tissue transcriptome studies can identify expression changes associated with pathology, however bulk represents a heterogeneous mix of cells and the proportion vary between samples by diagnosis. It is imperative to account for cell in such studies, which typically rely on type marker genes samples. Isolation sorted populations characterize profiles CNS types improve knowledge genes. We aim isolate from fresh surgical greater numbers older assess profile context sex APOE genotype,...
Alzheimer's disease is pathologically defined by the presence of extracellular amyloid beta plaques and intracellular tau tangles, resulting in neurodegeneration reactive gliosis affected brain regions such as temporal cortex (TCX). The degree distribution AD pathology can be Braak stage (tau) Thal phase (amyloid). Brain tissue comprised multiple cell types that have different molecular profiles, proportions which vary between individuals response to disease; creating challenges for...
Abstract Background Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of blood‐brain‐barrier (BBB) properties. The breakdown BBB in Alzheimer’s disease (AD) well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU alterations observed AD brains are also detected from living patients unknown. Further, these perturbations require further investigation different model...
Abstract Background Alzheimer’s disease (AD) is a complex, multicellular with immunological and genetic components. Previous studies demonstrated associations between AD the missense variants ABI3‐rs616338‐T PLCG2‐rs72824905‐G. The perturbed expression of these genes has been to disrupt microglial function. To date, transcriptomic profiles variant carriers in context subtype state have not explored human brain. This represents knowledge gap our understanding risk resilience. We developed...
Abstract Background Recent studies increased the number of genes that are associated with co‐existence vascular pathologies and Alzheimer’s disease (AD). However, biological functions mechanism action by which they contribute to pathology still be further elucidated. Therefore, animal models allow streamlined large‐throughput functional screens in a biologically relevant manner essential. Towards this goal, we generated adult zebrafish amyloid toxicity functionally analyze candidate how...
Abstract Background Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate role GVU BBB breakdown in Alzheimer’s disease (AD), precise molecular changes contributing to its pathophysiology are unclear. Method We performed single nucleus RNA sequencing (snRNAseq) temporal cortex tissue 24 AD control brains...
Abstract Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by cell‐type‐specific tau lesions in neurons and glia. Using bulk brain RNAseq, we previously identified PSP‐associated genes co‐expression networks that are enriched with cell‐type marker genes. We extended our work to identify expression perturbations PSP using systems approach vivo validations model system. Method Single‐nucleus RNAseq (snRNAseq) was performed 33 frozen temporal cortex...
Tau neurofibrillary tangles and senile plaques comprised of insoluble amyloid beta are the major histopathological hallmarks Alzheimer's disease (AD). More than 85% autopsy-confirmed AD cases also exhibit some degree cerebral angiopathy (CAA), which is characterized by peptide deposits predominantly in blood vessels meningeal intracerebral vessels. Consequently, CAA predisposes individuals with to infarction hemorrhages, accounting for ∼20% elderly, could lead faster cognitive decline...