Background: Notochordal cells (NCs) present in the nucleus pulposus (NP) of the developing human intervertebral disc (IVD) disappear during the first decade of life. This loss coincides with the onset of IVD degeneration, therefore these cells are hypothesized to be important in NP homeostasis. Putative NC-derived (CD24) and progenitor (TIE2/GD2) cell sub-populations have previously been identified in the adult human NP, but their characteristics have yet to be compared.
View Article and Find Full Text PDFBasal forebrain cholinergic neurons project to the hippocampus and cortex, are critical for learning and memory, and are central to the pathogenesis of Alzheimer's disease (AD). GWAS have consistently shown that genomic variants at the gene locus are associated with significant increased risk of AD. GWAS studies have also shown that genetic variants in endocytosis genes, including , significantly increase susceptibility to AD.
View Article and Find Full Text PDFIn recent years, microglia have been highlighted for playing integral roles in neurodegenerative diseases, like glaucoma. To better understand the role of microglia during chronic ocular hypertension, we depleted microglia from aged (9-12 months old) DBA/2 J (D2) mice, which exhibit age-related increases in intraocular pressure, using a dietary CSF1R antagonist, PLX5622. Retinal ganglion cell (RGC) somas were counted, and optic nerve cross-sections stained and assessed for glaucomatous damage.
View Article and Find Full Text PDFGlaucoma is a neurodegenerative disease that leads to the death of retinal ganglion cells (RGCs). A growing body of literature suggests a role for neuroinflammation in RGC death after glaucoma-relevant insults. For instance, it was shown that deficiency of three proinflammatory cytokines, complement component 1, subcomponent q ( ), interleukin 1 alpha ( ), and tumor necrosis factor ( ), resulted in near complete protection of RGCs after two glaucoma-relevant insults, optic nerve injury and ocular hypertension.
View Article and Find Full Text PDFHundreds of spores of are inhaled daily by human beings, representing a constant, possibly fatal, threat to respiratory health. The small size of spores suggests that interactions with alveolar epithelial cells (AECs) are frequent; thus, we hypothesized that spore uptake by AECs is important for driving fungal killing and susceptibility to -related disease. Using single-cell approaches to measure spore uptake and its outcomes , we demonstrate that spores are internalized and killed by AECs during whole-animal infection.
View Article and Find Full Text PDFIntroduction: MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer's disease (LOAD) more accurately.
Methods: We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aβ). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD).
Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection.
Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology.
Age is the largest risk factor for developing Alzheimer's disease (AD), a neurodegenerative disorder that causes a progressive and severe dementia. The underlying cause of cognitive deficits seen in AD is thought to be the disconnection of neural circuits that control memory and executive functions. Insight into the mechanisms by which AD diverges from normal aging will require identifying precisely which cellular events are driven by aging and which are impacted by AD-related pathologies.
View Article and Find Full Text PDFIntroduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.
Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.
Introduction: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation.
Methods: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.
Background: Age is the principal risk factor for neurodegeneration in both the retina and brain. The retina and brain share many biological properties; thus, insights into retinal aging and degeneration may shed light onto similar processes in the brain. Genetic makeup strongly influences susceptibility to age-related retinal disease.
View Article and Find Full Text PDFIn recent years, microglia have been highlighted for playing integral roles in neurodegenerative diseases, like glaucoma. To better understand the role of microglia during chronic ocular hypertension, we depleted microglia from aged (9-12 months old) DBA/2J (D2) mice, which exhibit age-related increases in intraocular pressure, using a dietary CSF1R antagonist, PLX5622. Retinal ganglion cell (RGC) somas were counted, and optic nerve cross-sections stained and assessed for glaucomatous damage.
View Article and Find Full Text PDFIntroduction: In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related dementias (ADRD) field.
Methods: During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus.
Background: The kidney contains distinct glomerular and tubulointerstitial compartments with diverse cell types and extracellular matrix components. The role of immune cells in glomerular environment is crucial for dampening inflammation and maintaining homeostasis. Macrophages are innate immune cells that are influenced by their tissue microenvironment.
View Article and Find Full Text PDFScope: Disturbances in one-carbon metabolism contribute to nonalcoholic fatty liver disease (NAFLD) which encompasses steatosis, steatohepatitis, fibrosis, and cirrhosis. The goal is to examine impact of folate deficiency and the Mthfr variant on NAFLD.
Methods And Results: This study uses the new Mthfr mouse model for the human MTHFR variant.
Introduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.
Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.
Introduction: MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models.
Methods: We created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age.
Introduction: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species provides a promising entry point for translation. METHODS: We investigated differences of serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.
View Article and Find Full Text PDFBackground: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 () being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection.
Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and h mice, and were verified by transcriptomics, and immunopathology.
The disconnection of neuronal circuitry through synaptic loss is presumed to be a major driver of age-related cognitive decline. Age-related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through maintenance or vulnerability of synaptic connections remains unknown. Previous work using rodent and primate models leveraged various techniques to imply that age-related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus.
View Article and Find Full Text PDFIntroduction: Human data suggest susceptibility and resilience to features of Alzheimer's disease (AD) such as microglia activation and synaptic dysfunction are under genetic control. However, causal relationships between these processes, and how genomic diversity modulates them remain systemically underexplored in mouse models.
Methods: AD-vulnerable hippocampal neurons were virally labeled in inbred (C57BL/6J) and wild-derived (PWK/PhJ) APP/PS1 and wild-type mice, and brain microglia depleted from 4 to 8 months of age.
The disconnection of neuronal circuits through synaptic loss is presumed to be a major driver of age-related cognitive decline. Age-related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through synaptic structural mechanisms remains unknown. Previous work using rodent and primate models leveraged various techniques to suggest that age-related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus.
View Article and Find Full Text PDFCommon features of Alzheimer's disease (AD) include amyloid pathology, microglia activation and synaptic dysfunction, however, the causal relationships amongst them remains unclear. Further, human data suggest susceptibility and resilience to AD neuropathology is controlled by genetic context, a factor underexplored in mouse models. To this end, we leveraged viral strategies to label an AD-vulnerable neuronal circuit in CA1 dendrites projecting to the frontal cortex in genetically diverse C57BL/6J (B6) and PWK/PhJ (PWK) mouse strains and used PLX5622 to non-invasively deplete brain microglia.
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