A5063586680- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Nuclear Receptors and Signaling
- Bioinformatics and Genomic Networks
- Computational Drug Discovery Methods
- Metabolomics and Mass Spectrometry Studies
- GDF15 and Related Biomarkers
- Tryptophan and brain disorders
- Neurological Disease Mechanisms and Treatments
- Folate and B Vitamins Research
- Cholinesterase and Neurodegenerative Diseases
- Biological Research and Disease Studies
- Peroxisome Proliferator-Activated Receptors
- Cancer Research and Treatments
- Inflammation biomarkers and pathways
- Epigenetics and DNA Methylation
- Medicinal Plants and Neuroprotection
- interferon and immune responses
- Dementia and Cognitive Impairment Research
- Animal Genetics and Reproduction
- Adipose Tissue and Metabolism
- Molecular Biology Techniques and Applications
- Single-cell and spatial transcriptomics
- Genetic Associations and Epidemiology
- Drug Transport and Resistance Mechanisms
Jackson Laboratory
2014-2024
Jackson Laboratories (India)
2021
University of Arkansas for Medical Sciences
1998
National Institutes of Health
1996-1997
The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization the model(s) being used. There are numerous that have been generated study Alzheimer's disease (AD) and underlying pathogenesis disease. While transgenic instrumental understanding AD mechanisms risk factors, they limited degree characteristics displayed comparison with humans, full spectrum effects has yet be recapitulated a single mouse model. Model...
Transgenesis has been a mainstay of mouse genetics for over 30 yr, providing numerous models human disease and critical genetic tools in widespread use today. Generated through the random integration DNA fragments into host genome, transgenesis can lead to insertional mutagenesis if coding gene or an essential element is disrupted, there evidence that larger scale structural variation accompany integration. The insertion sites only tiny fraction thousands transgenic lines existence have...
Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) upregulated predominantly perivascular macrophages and, to a lesser extent, fibroblasts. Perivascular SPP1 required for microglia engulf upregulate phagocytic markers including C1qa, Grn...
Abstract Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances our understanding basic biological mechanisms underlying AD, we do not know how to prevent it, nor have an approved disease‐modifying intervention. Both are essential slow or stop growth dementia prevalence. While current animal models AD provided novel insights into mechanisms, thus far, they been successfully used predict effectiveness therapies that moved clinical...
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression mutated transgenes have yielded key insights mechanisms disease, those are subject to artifacts, including random genetic integration transgene, ectopic expression and non-physiological protein levels. The engineering novel using knock-in approaches addresses some limitations. With...
Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in pathways conserved across species can facilitate translation.
Abstract INTRODUCTION MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease) is creating distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory progression of late‐onset disease (LOAD) more accurately. METHODS We created LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, humanized amyloid‐beta (Aβ). Mice were subjected a control diet or high‐fat/high‐sugar (LOAD2+HFD). assessed...
Abstract Background Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia worldwide. To date, animal models have focused on rare familial mutations, due to a lack frank neuropathology from based genes. Recent multi-cohort studies postmortem human brain transcriptomes identified set 30 gene co-expression modules associated with LOAD, providing molecular catalog relevant endophenotypes. Results This resource enables precise gene-based alignment between new and signatures...
Late-onset Alzheimer’s disease (AD; LOAD) is the most common human neurodegenerative disease, however, availability and efficacy of disease-modifying interventions severely lacking. Despite exceptional efforts to understand progression via legacy amyloidogenic transgene mouse models, focus on translation with innovative strains that better model complexity AD required accelerate development future treatment modalities. LOAD within population a polygenic environmentally influenced many risk...
Introduction Restrictions on existing APOE mouse models have impacted research toward understanding the strongest genetic risk factor contributing to Alzheimer’s disease (AD) and dementia, ε4 , by hindering observation of a key, common genotype in humans – ε3/ε4 . Human studies are typically underpowered address allele as ε4/ε4 is rare, which leaves human unsupported evaluate molecular pathological for AD dementia. Methods As part MODEL-AD, we created validated new versions humanized ε3/ε3...
Abstract INTRODUCTION Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in etiology Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as field we had only limited success incorporating rich complexity human AD/ADRD genetics findings into our animal models these diseases. Our primary goal for gene replacement (GR)‐AD project is to develop mouse lines model closely possible. METHODS To do...
Variants identified in genome-wide association studies have implicated immune pathways the development of Alzheimer's disease (AD).Here, we investigated mechanistic basis for protection from AD associated with PLCc2 R522, a rare coding variant PLCG2 gene.We studied variant's role macrophages and microglia newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) knockin mice, which exhibit normal endogenous expression.In all models, cells expressing R522 mutation...
Abstract Introduction Preclinical testing in animal models is a critical component of the drug discovery and development process. While hundreds interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments models, none confirmed Alzheimer's disease (AD) clinical trials. Critically this lack translation to clinic points part issues with assays used, scientific rigor reproducibility during execution. In an effort improve translation, Testing Core (PTC) Model...
Multiple mutations have been described in the human GBA1 gene, which encodes lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous , linked to storage disorder Gaucher’s disease (GD) distinct or heterozygous are associated with increased Parkinson’s (PD) risk. While numerous genes heritable PD, aggregate single greatest risk factor for development idiopathic PD. The...
Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority studies, to date, focused on use early-onset AD models. Here, we evaluate impact genetic factors late-onset (LOAD) mice fed with high fat/high sugar diet (HFD). We three created through IU/JAX/PITT MODEL-AD Center. These included combined model APOE4 and variant triggering receptor expressed...
Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms been functionally assessed for relevance and mechanism of action.
Expression of the N-methyl--aspartate (NMDA) receptor 2B (NR2B) subunit is neural-specific and differentially regulated. It expressed in forebrain cerebellar granule cells at early postnatal stages selectively repressed cerebellum after second week, where it replaced by NR2C subunit. This switch confers distinct properties to receptor. In order understand molecular mechanisms that regulate NR2B gene during development, we have isolated characterized promoter region gene. Two 5' noncoding...
Alzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, tau pathology, neuroinflammation, and neurodegeneration. Mouse models recapitulate some key features AD. For instance, the B6. APP/PS1 model (carrying human transgenes for mutant forms APP PSEN1) shows deposition neuroinflammation involving both astrocytes microglia beginning around 4–6 months age. However, significant pathology neurodegeneration are not apparent in this even when assessed at...
Molecular characterization of late-onset Alzheimer's disease (LOAD), the leading cause age-related dementia, has revealed transcripts, proteins, and pathway alterations associated with disease. Assessing these postmortem signatures LOAD in experimental model systems can further elucidate their relevance to origins progression. Model organisms engineered human genetic factors link disease-associated variants, especially when studies are designed leverage homology across species. Here we...
The fifth annual workshop on Principles and Techniques for Improving Preclinical Translation of Alzheimer's Disease Research was held in May 2023 at Jackson Laboratory Bar Harbor, Maine, USA. established 2018 to address training gaps preclinical translational studies disease (AD). In addition providing fundamental knowledge hands-on skills essential executing rigorous vivo that are designed facilitate translation, each year the aims provide insight state-of-the-field technological advances...
Heterozygous mutations in the GBA1 gene - encoding lysosomal glucocerebrosidase (GCase) are most common genetic risk factors for Parkinson's disease (PD). Experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable better understanding relationship aSyn activity, we developed characterized two mouse models that investigate pathology context reduced activity. The first model used constitutive overexpression wild-type...