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Theranostics 2022; 12(12):5504-5521. doi:10.7150/thno.72258 This issue Cite

Research Paper

A surrogate marker for very early-stage tau pathology is detectable by molecular magnetic resonance imaging

Parag Parekh^1*, Qingshan Mu^1*, Andrew Badachhape^1*, Rohan Bhavane², Mayank Srivastava², Laxman Devkota¹, Xianwei Sun¹, Prajwal Bhandari¹, Jason L. Eriksen³, Eric Tanifum⁴, Ketan Ghaghada⁴, Ananth Annapragada^4✉

1. Baylor College of Medicine, Houston, TX, USA
2. Texas Children's Hospital, Houston, TX, USA
3. College of Pharmacy, University of Houston, Houston, TX, USA
4. Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA
^*Contributed equally to this manuscript

✉ Corresponding author: annapragedu

Abstract

The abnormal phosphorylation of tau is a necessary precursor to the formation of tau fibrils, a marker of Alzheimer's disease. We hypothesize that hyperphosphorylative conditions may result in unique cell surface markers. We identify and demonstrate the utility of such surrogate markers to identify the hyperphosphorylative state.

Methods: Cell SELEX was used to identify novel thioaptamers specifically binding hyperphosphorylative cells. Cell surface vimentin was identified as a potential binding target of the aptamer. Novel molecular magnetic resonance imaging (M-MRI) probes using these aptamers and a small molecule ligand to vimentin were used for in vivo detection of this pre-pathological state.

Results: In a mouse model of pathological tau, we demonstrated in vivo visualization of the hyperphosphorylative state by M-MRI, enabling the identification at a pre-pathological stage of mice that develop frank tau pathology several months later. In vivo visualization of the hyperphosphorylative state by M-MRI was further validated in a second mouse model (APP/PS1) of Alzheimer's disease again identifying the mutants at a pre-pathological stage.

Conclusions: M-MRI of the hyperphosphorylative state identifies future tau pathology and could enable extremely early-stage diagnosis of Alzheimer's disease, at a pre-patholgical stage.

Keywords: Tau, Alzheimer's disease, Hyperphosphorylation, Magnetic Resonance Imaging (MRI), Thioaptamer, Withaferin A, Nanoparticle, Molecular Imaging

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