Plasma pTau markers correlate with an imaging surrogate marker of hyperphosphorylation in mouse models of Alzheimers disease

Abstract

BackgroundWe previously reported Cell surface vimentin (CSV) as a surrogate marker for cells in a hyperphosphorylative state, leading to pathological tau deposits in mouse models. Here were investigate the correlation between a Magnetic Resonance Imaging (MRI) marker of CSV and changes in the plasma pTau biomarkers at early stages of tau pathology. We studied total tau, ptau181 and ptau 231 in the plasma of mice at 2 and 5months of age prior to the formation of frank pathology, and with emerging pathology respectively, and compared them to the signal from the MRI marker of CSV.MethodTransgenic P301S and APP/PSEN1 mice and their wild‐type littermates were injected intravenously with liposomal nanoparticles bearing small molecule Withaferin (WNP) as a targeting ligand, and Gd/DOTA as an MRI readout, at 2‐ and 5‐ months of age. Animals (n=10 each) underwent magnetic resonance imaging (MRI) using T1 weighted sequences to visualize brain localization of CSV‐targeted liposomes. Blood was collected in EDTA tubes by puncture of facial vein post‐MRI scan. Plasma samples were centrifuged at 1000xg for 10mins at 4⁰C within 30mins of collection and stored at ‐80⁰C. Plasma concentrations of tau species were measured using the multiplex xMAP Luminex platform with kit‐based reagents, Milliplex for ptau181, total tau and Procartaplex for ptau231.ResultMRI signal enhancement was observed in 2‐month old transgenic mice but not in WT mice in both P301S and APP/PSEN1 AD models. Concurrently, we observed higher expression of ptau 181 in the TG mice over WT littermates. Similar results were also observed in the 5‐month old mice.ConclusionMRI with CSV targeted nanoparticles demonstrates brain signal that correlates with pTau181, consistent with the cell surface marker of hyperphosphorylation marking the same process that results in hyperphosphorylated tau species being formed in the transgenic mice. The results strengthen the mechanistic basis of a cell‐surface vimentin targeted agent being a suitable marker of very early‐stage development of tau pathology and furthermore demonstrates localization of the pathology. The use of readily available and relatively inexpensive MRI for this purpose has huge advantages over existing methods for the identification of early stage tau pathology.