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
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