Biology subjects

Reagan, A. M.

Publications and source records attributed to Reagan, A. M..

4 recordsLinked to original sources

bioRxiv2026

MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer's disease

Background: Late-onset Alzheimer's disease (LOAD) comprises more than 95% of all AD cases. Transgenic, overexpression animal models have off target side effects, do not effectively produce the heterogeneity observed clinically in LOAD patients, and are therefore not best suited for preclinical therapeutic development. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD) Consortium was established to develop novel mouse strains to model human-relevant genetic and environmental risk factors for LOAD. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate/methionine pathway. Variants in the MTHFR gene, notably 677C>T, are associated with ADRD, and we have previously shown the Mthfr677C>T mouse model phenocopies humans carrying the variant and develop cerebrovascular deficits. Methods: To examine the contributions of Mthfr677C>T in the context of late-onset Alzheimer's disease (LOAD), MODEL-AD created a novel mouse strain on the C57BL/6J (B6) background that was homozygous for Mthfr677C>T, in combination with humanized Abeta;, APOEe4, and Trem2*R47H (referred to as LOAD2.Mthfr677C>T). Mice were assessed over multiple ages for disease-relevant phenotypes. Regular behavior measurements and biometric samples were collected longitudinally to 24 months of age. Blood and brain tissue were collected for transcriptomics, proteomics, human disease correlation, and neuropathology. Results: Despite lacking hallmark pathologies such as amyloid deposition and significant neuroinflammation, compared to LOAD2 controls, LOAD2.Mthfr677C>T mice showed transcriptional and proteomic signatures in the brain that relate to the cerebrovasculature, myelination, and synaptic biology, similar to those seen in human LOAD patients. Conclusions: These data further support the use of the LOAD2.Mthfr677C>T mouse model to study aspects of ADRD such as cerebrovascular compromise.

neuroscience↗

bioRxiv2025

Retinal vascular dysfunction in the Mthfr677C>T mouse model of cerebrovascular disease

IntroductionInvestigating retinal biomarkers for Alzheimers disease (AD) and related dementias (RD), has increased significantly. We examine retinal vascular health in a mouse containing the ADRD risk variant Mthfr677C>Tto determine if changes in retina mirror similar changes in cerebrovasculature. MethodsMorphology and function of retinal vasculature and neurons were assessed using in vivo imaging, immunohistochemistry and pattern electroretinography. RNAscope and proteomics were employed to determine Mthfr gene expression and differential protein expression in mice carrying Mthfr677C>T. ResultsMice show reduced retinal vascular density and reduced perfusion rate in aging mice, mirroring previously published brain data. Mthfr is widely expressed and colocalizes with vascular cell markers. Proteomics identified common molecular signatures across brain and retina. DiscussionResults demonstrate that Mthfr-dependent vascular phenotypes occur in brain and retina similarly. These data suggest that assessing age and genetic-driven changes within retinal vasculature represents a minimally invasive method to predict AD-related cerebrovascular damage.

genetics↗

bioRxiv2024

Genetic context modulates aging and degeneration in the murine retina

BackgroundAge 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. However, studies investigating retinal aging have not sufficiently accounted for genetic diversity. Therefore, examining molecular aging in the retina across different genetic backgrounds will enhance our understanding of human-relevant aging and degeneration in both the retina and brain--potentially improving therapeutic approaches to these debilitating conditions. MethodsTranscriptomics and proteomics were employed to elucidate retinal aging signatures in nine genetically diverse mouse strains (C57BL/6J, 129S1/SvlmJ, NZO/HlLtJ, WSB/EiJ, CAST/EiJ, PWK/PhK, NOD/ShiLtJ, A/J, and BALB/cJ) across lifespan. These data predicted human disease-relevant changes in WSB and NZO strains. Accordingly, B6, WSB and NZO mice were subjected to human-relevant in vivo examinations at 4, 8, 12, and/or 18M, including: slit lamp, fundus imaging, optical coherence tomography, fluorescein angiography, and pattern/full-field electroretinography. Retinal morphology, vascular structure, and cell counts were assessed ex vivo. ResultsWe identified common molecular aging signatures across the nine mouse strains, which included genes associated with photoreceptor function and immune activation. Genetic background strongly modulated these aging signatures. Analysis of cell type-specific marker genes predicted age-related loss of photoreceptors and retinal ganglion cells (RGCs) in WSB and NZO, respectively. Fundus exams revealed retinitis pigmentosa-relevant pigmentary abnormalities in WSB retinas and diabetic retinopathy (DR)-relevant cotton wool spots and exudates in NZO retinas. Profound photoreceptor dysfunction and loss were confirmed in WSB. Molecular analyses indicated changes in photoreceptor-specific proteins prior to loss, suggesting photoreceptor-intrinsic dysfunction in WSB. In addition, age-associated RGC dysfunction, loss, and concomitant microvascular dysfunction was observed in NZO mice. Proteomic analyses revealed an early reduction in protective antioxidant processes, which may underlie increased susceptibility to DR-relevant pathology in NZO. ConclusionsGenetic context is a strong determinant of retinal aging, and our multi-omics resource can aid in understanding age-related diseases of the eye and brain. Our investigations identified and validated WSB and NZO mice as improved preclinical models relevant to common retinal neurodegenerative diseases.

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↗