Biology subjects

Eldridge, K.

Publications and source records attributed to Eldridge, K..

6 recordsLinked to original sources

bioRxiv2025

WSB.APP/PS1 mice develop age-dependent cerebral amyloid angiopathy, cerebrovascular deficits, and white matter damage, which are modified by humanized APOE alleles.

INTRODUCTIONGrowing evidence suggests cerebrovascular deficits, including cerebral amyloid angiopathy (CAA), play a key role in Alzheimers disease (AD) pathogenesis. However, these facets of AD are not well understood, due in part to the lack of mouse models that develop robust vascular deficits and CAA. Here, we characterize human-relevant cerebrovascular phenotypes in WSB.APP/PS1 mice with and without humanized APOE alleles. METHODSAD-relevant cerebrovascular phenotypes in WSB, WSB.APP/PS1, WSB.APOE2/2APP/PS1, WSB.APOE3/3APP/PS1, and/or WSB.APOE4/4APP/PS1 mice were characterized using immunohistochemistry, transcriptomics, positron emission tomography/computed tomography, and ex-vivo analyses. RESULTSWSB.APP/PS1 mice exhibited age-related plaque deposition and CAA, significant transcriptomic overlap with human AD, myelin deficits, cerebrovascular/metabolic uncoupling, and altered cerebrovascular morphology. Aged WSB vasculature retained vasoreactivity, but exhibited increased stiffness. Compared to APOE2, APOE4 expression in WSB.APP/PS1 mice increased CAA and plaque-associated microglial area. DISCUSSIONThese data illustrate the utility of the WSB genetic context to model CAA and uncover vascular contributions to AD. HighlightsO_LIWSB.APP/PS1 mice developed CAA with age. C_LIO_LITranscriptomic profiling revealed significant molecular overlap between human AD and WSB.APP/PS1 brains. C_LIO_LITranscriptomics and immunofluorescence suggested age-related myelin deficits in WSB.APP/PS1 brains. C_LIO_LIWSB.APP/PS1 brains exhibited neurovascular uncoupling, changes in vascular volume and surface area, and increased permeability changes. C_LIO_LIWSB.APP/PS1 cerebrovasculature was resilient to loss of responsivity with age but exhibited increased vascular stiffness. C_LIO_LIHumanized APOE {varepsilon}4 alleles significantly increased CAA and parenchymal plaque-associated microglial area in WSB.APP/PS1 mice. C_LI Research in ContextO_LISystematic review: The authors characterized WSB.APP/PS1 as a unique human-relevant model of Alzheimers Disease and explored several facets of cerebrovascular deficits. C_LIO_LIInterpretation: WSB and/or WSB.APP/PS1 mice exhibited human-relevant vascular phenotypes, including CAA, neurovascular uncoupling, increased vascular tree volume, vascular stiffness, and resilience to age-related loss of responsivity. Furthermore, the transcriptomic profile of WSB.APP/PS1 brains significantly overlaps with signatures observed in human AD. WSB.APP/PS1 brains exhibited myelin deficits with age. Furthermore, humanized APOE {varepsilon}2, {varepsilon}3, and {varepsilon}4 alleles significantly modified WSB.APP/PS1 susceptibility to CAA, plaque deposition, and plaque-associated microglial area. C_LIO_LIFuture Directions: The WSB genetic context will be leveraged to identify specific molecular mechanisms associated with cerebrovascular deficits in AD. C_LI

neuroscience↗

bioRxiv2023

Characterizing Molecular and Synaptic Signatures in Mouse Models of Late-Onset Alzheimer's Disease Independent of Amyloid and Tau Pathology

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSMODEL-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. METHODSWe 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. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior. RESULTSBy 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain A{beta}42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks. DISCUSSIONCollectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.

neuroscience↗

bioRxiv2023

Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction

STRUCTURED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSAlzheimers disease (AD) is the most common cause of dementia worldwide, with apolipoprotein {varepsilon}4 (APOE{varepsilon}4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODSPET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTSAll hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOE{varepsilon}4/{varepsilon}4 exhibited significant Type-1 uncoupling ({downarrow} glucose uptake, {uparrow} perfusion) at 8 and 12 mo, while APOE{varepsilon}3/{varepsilon}4 demonstrated Type-2 uncoupling ({uparrow} glucose uptake, {downarrow} perfusion), while immunopathology confirmed cell specific contributions. DISCUSSIONThis work highlights APOE{varepsilon}4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.

neuroscience↗

bioRxiv2023

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease

The 5xFAD mouse model is a popular model of familial Alzheimers Disease (AD) that is characterized by early beta-amyloid (A{beta}) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Male and female 5xFAD and WT littermates underwent in vivo 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter. With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan. While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing A{beta} deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of the motor and visual cortex and increased vessel lengths alongside decreased collaterals coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing A{beta} deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

neuroscience↗

bioRxiv2022

Plcg2M28L interacts with high fat-high sugar diet to accelerate Alzheimers disease-relevant phenotypes in mice

Obesity is recognized as a significant risk factor for Alzheimers disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies to date have focused on the use of early-onset AD models. Here we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed a high fat/high sugar diet. We focused on three mouse models created through the IU/JAX/Pitt MODEL-AD Center, LOAD1, LOAD1.Plcg2M28L and LOAD1.Mthfr677C>T. At 2 months of age, animals were placed on a high fat/high sugar diet (HFD) that induces obesity, or a control diet (CD) that does not, until 12 months of age. Throughout the study, blood was collected to assess cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. At the completion of the study, blood and brains were collected for analysis. As expected, animals fed the HFD, regardless of genotype or sex, showed a significant increase in body weight compared to those fed the CD. Glucose and cholesterol increased as a function of HFD as well. Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density as well as alterations in regional brain glucose and perfusion when on a HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr677C>T animals when fed a HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr677C>T or LOAD1 animals showed transcriptomics correlations to human AD modules. Our results show HFD affects brain health in a genotype-specific manner. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

neuroscience↗

bioRxiv2021

The 677C>T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimers disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677C>T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C>T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C>T allele on the C57BL/6J background (Mthfr677C>T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C>T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity as well as critical metabolites in the folate and methionine cycles are reduced in the Mthfr677C>T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data suggest critical perturbations to cerebrovascular function in Mthfr677C>T mice supporting its use as a model for preclinical studies of VCID.

genetics↗