Antibody Therapy Against Tau Pathology Improves Neuronal Transport as Assessed In Vivo by Tract-Tracing Manganese-Enhanced MRI
Maria F Baron1, Hameetha Banu Rajamohamed Sait2, Wajitha J RajaMohamed Sait 2, D Minh Hoang1, Einar M Sigurdsson2,3, and Youssef Z Wadghiri1

1Radiology, Center for Advanced Imaging Innovation & Research (CAI2R) and Bernard and Irene Schwartz Center for Biomedical Imaging, NYU School of Medicine, New York, NY, United States, 2Neuroscience and Physiology, NYU School of Medicine, New York, NY, United States, 3Psychiatry, NYU School of Medicine, New York, NY, United States

Synopsis

Immunotherapies to target Alzheimer’s pathology have been developed in recent years. Amyloid‐ß centric approaches have shown limited efficacy, resulting in emphasis on immunotherapies for clearing pathological tau protein (τ-Thx). Our group has demonstrated that Tract‐Tracing Manganese Enhanced MRI (TT-MEMRI) is effective to monitor the deleterious effect of tau pathology on neuronal transport in transgenic (τ-Tg) mice. In this study, our TT-MEMRI protocol was used effectively to show the efficacy of acute tau antibody therapy in an advanced stage of tauopathy in the Tg model we previously characterized with TT-MEMRI. Specifically, neuronal transport can be restored after a four-week treatment period.

Introduction

Alzheimer’s disease (AD) is the most common cause of progressive dementia and is associated with extensive deposition of amyloid-ß peptide and hyperphosphorylated tau protein. Immunotherapies to target both pathologies have been developed in recent years, but so far amyloid-ß centric approaches that reached Phase III clinical trials have shown limited efficacy, leading to a shift in focus of the pharmaceutical industry to tau-based immunotherapies aimed at clearing pathological tau protein [1,2]. Our group has demonstrated that Tract-Tracing Manganese-Enhanced Magnetic Resonance Imaging (TT-MEMRI) is a very sensitive method to evaluate the deleterious effect of tau pathology on neuronal transport in transgenic mouse models of tauopathy. Our multi-session imaging method proved very successful in monitoring the progression of tauopathy with minimal risks to mice evaluated over a period of several months with multiple MR examinations [3,4]. To this effect, our TT-MEMRI protocol has been routinely used to assess the efficacy of tau-antibody therapy developed by our colleagues [5,6]. In this study, we investigated the potential benefit of weekly passive immunization within a four-week period on modifying the disease progression and altering the course of the associated impairment in neuronal transport seen in aging transgenic mouse model of tauopathy and that we previously documented using our TT-MEMRI protocol [4].

Methods

Seventeen homozygous JNPL3 transgenic mice modeling tauopathy [7], aged 13 months, underwent our TT-MEMRI protocol prior to treatment to establish the baseline and 4 weeks after being subjected to immunotherapy on a weekly basis. Eight of these mice received a tau monoclonal antibody (τ-mAb, 10 mg/kg of weekly intraperitoneal injection), while the other nine mice received immunoglobulin G as a controls. Imaging studies were performed on a 7-T micro-MRI, using a 3D T1-SPGR sequence. Mice were imaged pre-injection, then intranasally instilled with 1.5 ul of 5M MnCl2, under isoflurane anesthesia. Image sets were acquired at 1, 4, 8, 12, 24, 36, 48 hours, and finally at 7 days for a total of nine time points (Figure 1). Image datasets were registered with Amira 5.0 and predefined ROI’s for the glomerular layer were processed using ImageJ. Normalized measurements for each mouse were plotted and fitted to a tract tracing bolus model based on the Fokker-Planck equation [3] using MATLAB. This time-curve fitting allows for the unbiased characterization of the TT-MEMRI bolus of each subject by estimating the time to peak of intensity, peak intensity value of the bolus of manganese and maximal value of the ascending slope of uptake.

Results & Discussion

The mouse control group subjected to IgG injections demonstrated a significant decline in the peak value of manganese uptake after 4 weeks reflecting a progression of transport impairment expected in this mouse model in absence of effective treatment based on our prior findings [4] (Figure 2.A; **p<0.01, paired t-test). On the other hand, the same peak value parameter did not decay in the transgenic mouse group treated during the four week period with the τ-mAb which resulted in a significant difference compared to the IgG treated group (Figure 2.A; ## p<0.01, unpaired t-test). A significant decrease in the time to peak (**p<0.01, paired t-test; Figure 2.B) and an increase in maximal slope of manganese uptake (*p<0.05, paired t-test; Figure 2.C) were observed in the glomerular layer of the tau mAb-treated mice after the same four week period. These results taken together with our previous TT-MEMRI-based characterization of the same JNPL3 Tau transgenic mouse model indicate that the four weeks of treatment against tau pathology using passive immunization can lead to effective improvement in neuronal transport detectable by our protocol.

Conclusions

Our results demonstrate that antibodies targeting tau pathology can restore neuronal transport in the advanced stage of tauopathy after only a four week treatment. Our in vivo and noninvasive TT-MEMRI protocol proved to be a sensitive technique to assess the improvement in neuronal transport resulting from the treatment. Olfactory sections from these mice are currently being analyzed to assess the correlation of the improvement in axonal transport seen in our in vivo results with the load of tau lesions in both groups.

Clinical Relevance

This study provides evidence that TT-MEMRI is a useful, noninvasive tool to assess the efficacy of novel antibody therapies in the preclinical setting. The tau monoclonal antibody strategy shows promise as a therapy to clear tau pathology and improve neuronal transport.

Acknowledgements

This work was supported by: NIH AG020197, AG032611, NS077239 E.M.S.; the Alzheimer’s Association IIRG-08-91618 to Y.Z.W.; the American Health Assistance Foundation A2008-155 to Y.Z.W and the NYU Applied Research Support Fund to Y.Z.W. as well as funding from NIH/NCI 5P30CA016087-32 & NIH P41 EB017183. NYU technology on tau immunotherapy is licensed to and is being co-developed with H. Lundbeck A/S. E.M.S. is an inventor on relevant tau immunotherapy patents assigned to NYU and licensed to H. Lundbeck A/S.

References

1. Asuni AA et al., J Neurosci. 27(34):9115-29 (2007). 2. Pedersen JT & Sigurdsson EM, Trends Mol Med. 21(6), 394-402 (2015). 3. Bertrand et al., Current Medical Imaging Reviews 7, 16-27 (2011).; 4. Bertrand et al., Neuroimage 64C, 693-702 (2012). 5. Congdon EE et al., J. Biol. Chem. 288:35452-65 (2013). 6. Gu J et al., J. Biol. Chem. 2013 288: 33081-95 (2013). 7. Lewis et al., Genet. 25, 402–405 (2000).

Figures

Horizontal slice from 150µm isotropic 3D whole head dataset with insert zooming on signal enhancement progression (red arrows) induced by manganese uptake and intra-neuronal transport through the olfactory bulb. This is achieved thanks to our 9 time points MEMRI protocol (Pre-injection scan not shown but similar in appearance to T=7days).

The significant differences of the parameters defining the time-curve response found in τ-mAb treated mice (blue) compared to IgG controls (red) indicate a prevention of the transport impairment thanks to the effect of immunotherapy. A) The Pk-v decrease in Ig-treated control (red) reflects the expected decline due to Tauopathy progression.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
0801