A novel MRI contrast agent for identifying hyperphosphorylative neurons as a marker of future tau pathology

Abstract

AbstractBackgroundHyperphosphorylated tau (pTau) is a precursor to tau tangle formation in Alzheimer's disease (AD). We have identified aptamers that bind to specific cell membrane receptors of human neuronal cells that are hyperphosphorylating tau. In this work, we built a novel targeted nanoparticle magnetic resonance imaging (MRI) contrast agent, TauX, that binds such neurons, and tested its efficacy in vivo in the P301S mouse model of tau pathology.MethodDNA aptamers preferentially binding on the cell membrane of hyperphosphorylative SH‐SY5Y cells were selected using a modified SELEX protocol. Mass spectrometric proteomic analysis of the bound aptamers was used to identify the binding targets on the cell‐surface, and target presence was validated on both mouse and Alzheimer’s disease patient brain tissues. P301S transgenic mice (n=8) and age‐matched wild type mice (n=6) were intravenously injected TauX contrast agent and imaged by MRI using a T1‐weighted spin‐echo (T1w‐SE) sequence at 2 months of age. An additional control group of transgenic mice (n=8) received untargeted gadolinium nanoparticle contrast agent. T1‐weighted images were acquired on 1T MRI scanner at pre‐ and 4 days post‐contrast injection. Receiver operator characteristic (ROC) curves were generated with a six‐point ordinal scale to assess sensitivity and specificity for TauX. Mice were aged to 8 months and their brains were histologically assessed with AT100 antibody to confirm pTau pathology.ResultTauX‐enhanced post‐contrast images showed MR signal enhancement in most of the transgenic mice that went on to develop tau pathology 4‐6 months later, but not in wild type animals lacking tau pathology (Figure 1). Transgenic mice given untargeted nanoparticle contrast also did not show MR signal enhancement (Figure 1). AT100 staining of P301S cortical brain sections demonstrated elevated pTau levels related to wild type counterparts (Figure 2). ROC curve constructed over the entire tested group, including controls, showed overall AUC and accuracy ∼0.8 (Figure 3).ConclusionA novel MRI contrast agent that can identify mice that develop tau pathology several months in the future has been demonstrated. If successful in humans, this agent could advance the identification of patients at risk of tau pathology to a very early pre‐symptomatic stage of the disease.