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

Badachhape, A. A.; Bhandari, P.; Khan, R.; Bhavane, R.; Menon, R.; Parekh, P.; Admane, P.; Ngan, E.; Srivastava, M.; Tanifum, E. A.; Annapragada, A. V.; Ritzel, R. M.; Ghaghada, K. B.

doi:10.64898/2026.10.27.761963

bioRxiv · 10.64898/2026.10.27.761963

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

Badachhape, A. A.·Bhandari, P.·Khan, R.·Bhavane, R.·Menon, R.·Parekh, P.·Admane, P.·Ngan, E.·Srivastava, M.·Tanifum, E. A.·Annapragada, A. V.·Ritzel, R. M.·Ghaghada, K. B.

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Abstract

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.

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Badachhape, A. A., Bhandari, P., Khan, R., Bhavane, R., Menon, R., Parekh, P., Admane, P., Ngan, E., Srivastava, M., Tanifum, E. A., Annapragada, A. V., Ritzel, R. M., Ghaghada, K. B.. 2026-11-01. Molecular MRI of Neuroinflammation in Alzheimer's Disease using a Folate-targeted Nanoprobe. https://doi.org/10.64898/2026.10.27.761963

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