Biology subjects

Ghaghada, K. B.

Publications and source records attributed to Ghaghada, K. B..

3 recordsLinked to original sources

bioRxiv2026

Molecular MRI of Neuroinflammation in Alzheimer's Disease using a Folate-targeted Nanoprobe

Background: Neuroinflammation, driven by activated microglia, plays a central role in the pathogenesis of Alzheimer's disease (AD). Non-invasive imaging of neuroinflammation holds promise for advancing our understanding of disease mechanisms and evaluating anti-inflammatory therapeutic strategies. The folate receptor (FR), specifically its {beta} isoform, has been identified as a marker of pro-inflammatory myeloid cells in peripheral inflammatory diseases; however, its association with AD neuroinflammation remains unknown. In this work, we first determined FR expression in microglia in mouse models of AD and subsequently evaluated molecular MRI (mMRI) using a folate-targeted nanoprobe for in vivo imaging of the folate receptor expression. Methods and results: Microglial activation and FR expression in APP/PS1 and P301S transgenic mouse models of AD was measured using flow cytometry. A FR-targeted nanoprobe for mMRI was prepared by functionalizing high T1-relaxivity liposomal gadolinium nanoparticle with folic acid. Following intravenous injection, localization of the nanoprobe in the brains of aged transgenic and wild-type mice was measured using T1-weighted MRI. Post-mortem microscopy measured nanoprobe localization relative to microglia and amyloid pathology. In both mouse models, FR{beta} was significantly (p < 0.05) upregulated in pro-inflammatory microglia expressing TNF and IL-1{beta}. The folate-targeted nanoprobe demonstrated MR signal enhancement in the cortical and hippocampal regions of transgenic mice but not in wild type mice; non-targeted nanoprobe control did not demonstrate signal enhancement in brain of transgenic mice. Microscopy confirmed colocalization of FR-targeted nanoprobe with IBA1-positive microglia/macrophages and amyloid plaques. Conclusions: Pro-inflammatory microglia exhibit elevated levels of FR, and its measurement by non-invasive mMRI is a promising marker of neuroinflammation in AD.

neuroscience↗

bioRxiv2024

Accelerated amyloid deposition in SARS-CoV-2 infected mouse models of Alzheimer's disease

Familial Alzheimers disease (AD) involving known AD causing genes accounts for a small fraction of cases, the vast majority are sporadic. Neuroinflammation, secondary to viral infection, has been suggested as an initiating or accelerating factor. In this work we tested the hypothesis that SARS-CoV-2 (SCV2) viral infection accelerates the development of AD pathology in mouse models of AD. We profiled transcriptomic changes using transgenic APP/PSEN1 and P301S mouse models that develop AD pathology and k18hACE2 mice that express the humanized ACE2 receptor used by SCV2 to enter cells. This study identified the interferon and chemokine responses constituting key shared pathways between SCV2 infection and the development of AD pathology. Two transgenic mouse models of AD: APP/PSEN1 (develops amyloid pathology) and 3xTg AD (develops both amyloid and tau pathology) were crossed with k18-hACE2 mice to generate hybrid hACE2-3xTg and hACE2-APP/PSEN1 mice. Neuroinflammation and amyloid deposition in the brain of infected mice were imaged in vivo using molecular MRI (mMRI) probes and confirmed postmortem by histopathology. Results show that 11-14-month-old SCV2 infected hACE2-3xTg mice exhibit neuroinflammation 10 days post infection and 4-5-month-old hACE2-APP/PS1 hybrid mice develop amyloid deposits, while age-matched uninfected mice exhibit neither phenotype. This suggests that SCV2 infection could induce or accelerate AD when risk factors are present.

neuroscience↗

bioRxiv2021

HepT1-derived murine models of high-risk hepatoblastoma display vascular invasion, metastasis, and circulating tumor cells

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB. Summary StatementIn this work, we developed and thoroughly characterized several unique models of hepatoblastoma derived from the HepT1 cell line that show high-risk features.

cancer biology↗