Faculty Bibliography

J. Neurochem. (2011) 118, 658-667. ABSTRACT: Targeting hyperphosphorylated tau by immunotherapy is emerging as a promising approach to treat tauopathies such as Alzheimer's disease and frontotemporal dementia. We have previously reported that active tau immunization clears tau aggregates from the brain and attenuates or prevents functional impairments in two different tangle mouse models. Here, we assessed the efficacy of passive immunization with the PHF1 antibody, which targets a phospho-epitope within one of our active immunogens. Homozygous female tangle mice (JNPL3, 2-3 months) were injected intraperitoneally once per week with PHF1 or pooled mouse IgG (250 mug/125 muL; n = 10 per group) for a total of 13 injections. Their behavior was assessed at 5-6 months of age and brain tissue was subsequently harvested for analyses of treatment efficacy. The treated mice performed better than controls on the traverse beam task (p < 0.03), and had 58% less tau pathology in the dentate gyrus of the hippocampus (p = 0.02). As assessed by western blots, the antibody therapy reduced the levels of insoluble pathological tau by 14-27% (PHF1, p < 0.05; PHF1/total tau, p < 0.0001) and 34-45% (CP13 or CP13/total tau, p < 0.05). Levels of soluble tau and sarkosyl soluble tau were unchanged, compared with controls, as well as total tau levels in all the fractions. Plasma levels of PHF1 correlated inversely with tau pathology in the brainstem (p < 0.01), with a strong trend in the motor cortex (p < 0.06) as well as with insoluble total tau levels (p < 0.02), indicating that higher dose of antibodies may have a greater therapeutic effect. Significant correlation was also observed between performance on the traverse beam task and PHF1 immunoreactivity in the dentate gyrus (p < 0.05) as well as with insoluble PHF1/total tau ratio on western blots (p < 0.04). These results show that passive immunization with tau antibodies can decrease tau pathology and functional impairments in the JNPL3 model. Future studies will determine the feasibility of this approach with other monoclonals and in different tangle models in which thorough cognitive assessment can be performed

Background: Active anti-amyloid immunotherapy is a strategy developed against Alzheimer's disease.ApproacheswithAs1-42 orK6As1-30 immunogens in an adjuvant decrease amyloid-s burden and prevent cognitive decline in transgenic mice (Asuni et al, 2006). However, clinical trials of As1-42 immunotherapy have induced side effects like encephalitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). Mouse lemurs can develop As plaques with age (Mestre-Frances et al, 2000). Such a primate modelmay bemore predictive than rodents of human side effects.We studied, by magnetic resonance imaging (MRI), immunotherapies in these primates. Methods: A first cohort was used to compare K6As1-30 (n = 4; 5.8 +/- 0.2 years) and As1-42 (n = 4; 5.9 +/- 0.2 years) immunogens in alum adjuvant. Asecond cohortwas used to evaluateK6As1-30 (n=6; 4.660.2 years) compared to adjuvant alone (n = 6; 4.7 +/- 0.3 years). All the animals were followed- up by MRI (7T PharmaScan-Bruker) to evaluate neuroinflammation, microhemorrhages and other forms of iron deposition, with T2-weighted and T2*-weighted sequences (resolution=(234x234x234)mm³). The hypointense regions from T2*-weighted images were quantified and evaluate by histology. A complementary study of age effectwas performedwith twenty other naive animals (1.5 to 4.9 years). Results: The T2-weighted images did not show any neuroinflammation during immunization, irrespective of the immunogen. Microhemorrhages were detected in the cerebral parenchyma at the histological analysis of the first cohort. The animals treated with K6As1-30 presented less microhemorrhages compared to those treated with As1-42 vaccine (Mann-Whitney, p < 0.05). These small microhemorrhages were not detected on the T2*-weighted images. However hypointense signalwas detected on MRI and corresponded to iron deposits in the choroid plexus. Its volume increasedwith natural aging (r= 0.60; p< 0.001) and withAs1-42 compared to K6As1-30 treatment (ANOVA, p < 0.05). No difference was detected between K6As1-30 and adjuvant alone. Conclusions: The immunotherapies studied in the mouse lemur primate did not lead to any MRI sign of neuroinflammation. The K6As1-30 strategy appears to be safer than theAs1-42 strategy as it provokes less microhemorrhages in the cerebral parenchyma and less iron deposits in the choroid plexus

Background: Active anti-amyloid immunotherapy is a strategy developed againstAlzheimer's disease.ApproacheswithAs1-42 orK6As1-30 immunogens in an adjuvant decrease amyloid-s burden and prevent cognitive decline in transgenic mice (Asuni et al, 2006). However, clinical trials of As1-42 immunotherapy have induced side effects like encephalitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). Mouse lemurs can develop As plaques with age (Mestre-Frances et al, 2000). Such a primate modelmay be more predictive than rodents of human side effects.We studied, by magnetic resonance imaging (MRI), immunotherapies in these primates. Methods: A first cohort was used to compare K6As1-30 (n = 4; 5.8 6 0.2years) and As1-42 (n = 4; 5.96 0.2years) immunogens in alumadjuvant. Asecond cohortwas used to evaluate K6As1-30 (n=6; 4.660.2years) compared to adjuvant alone (n = 6; 4.7 6 0.3years). All the animals were followed- up by MRI (7T PharmaScan-Bruker) to evaluate neuroinflammation, microhemorrhages and other forms of iron deposition, with T2-weighted and T2*-weighted sequences (resolution = (234x234x234)Amm3). The hypointense regions from T2*-weighted images were quantified and evaluate by histology. A complementary study of age effect was performed with twenty other naive animals (1.5 to 4.9years). Results: TheT2-weighted images did not show any neuroinflammation during immunization, irrespective of the immunogen. Microhemorrhages were detected in the cerebral parenchyma at the histological analysis of the first cohort. The animals treated with K6As1-30 presented less microhemorrhages compared to those treated with As1-42 vaccine (Mann-Whitney, p < 0.05). These small microhemorrhages were not detected on the T2*-weighted images. However hypointense signal was detected onMRI and corresponded to iron deposits in the choroid plexus. Its volume increased with natural aging (r=0.60; p<0.001) and with As1-42 compared toK6As1-30 treatment (ANOVA, p<0.05).No difference was detected between K6As1-30 and adjuvant alone. Conclusions: The immunotherapies studied in the mouse lemur primate did not lead to any MRI sign of neuroinflammation. The K6As1-30 strategy appears to be safer than the As1-42 strategy as it provokes less microhemorrhages in the cerebral parenchyma and less iron deposits in the choroid plexus

Background: Immunotherapy targeting pathological tau is emerging as a promising approach to treat tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia. We have previously shown that prophylactic active or passive tau immunotherapy, starting at 2-3 months of age, clears tau pathology and improves function (Asuni A. et al., J. Neurosci. 2007, Boutajangout A. et al., J. Neurosci. 2010, Boutajangout A. et al., ICAD 2010). Here we assessed if a phospho-specific monoclonal, 4E6G7, targeting the same epitope, would be efficacious if treatment commenced at an advanced stage of tau pathology (8-9 months). Methods: htau/PS1 mice without mouse tau protein (8-9 months) were injected intraperitoneally (250 mg/125 ml) once per week with a novel phospho- specific tau monoclonal, 4E6G7 (n = 9) or pooled mouse IgG (n = 10) for a total of 13 injections. Their behavior was analyzed at 11-12 months of age and brain tissue subsequently harvested for analyses of treatment efficacy. Results: The immunized mice (n = 7-8) performed substantially better than controls (n = 6) on the Radial Arm Maze (p < 0.0001; post hoc, p < 0.01-0.001 on days 2, 3, 5-9), the Closed Field Symmetrical Maze with 35-69% fewer errors in simple, intermediate and complex tasks (p < 0.05-0.003), and the Object Recognition Task (63% time spent with a novel object vs. 46% for controls, p < 0.05). The groups did not differ in various sensorimotor tasks, indicating that the robust cognitive improvements cannot be explained by sensorimotor effects, which further strengthens our results. Interestingly, more controls died during the study (40%) than immunized mice (22%), providing an additional support for the beneficial effect of the monoclonal tau antibody. Histological and biochemical analyses are underway. Conclusions: These results indicate pronounced efficacy of passive tau immunotherapy at an advanced stage of tauopathy, which suggests that this approach may be beneficial after clinical onset of AD and other tauopathies

Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-beta (Abeta) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first Abeta vaccination trial suggest that this approach has limited effect on tau pathology and that Abeta plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe whether targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L presenilin mutation. Here, we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future

Alzheimer's disease (AD) is a member of a category of neurodegenerative diseases characterized by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In the case of AD the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is an essential part of the pathology. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror different aspects of AD pathology. Perhaps the most exciting of these approaches is immunomodulation. Vaccination is currently being tried for a range of age associated CNS disorders with great success being reported in many transgenic mouse models. However, there is a discrepancy between these results and current human clinical trials which highlights the limitations of current models and also uncertainties in our understanding of the underlying pathogenesis of AD. No current AD Tg mouse model exactly reflects all aspects of the human disease. Since the underlying etiology of sporadic AD is unknown, the process of creating better Tg models is in constant evolution. This is an essential goal since it will be necessary to develop therapeutic approaches which will be highly effective in humans

Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid beta peptide is converted into oligomeric/fibrillar amyloid beta. The oligomeric forms of amyloid beta have been hypothesized to be the most toxic, whereas fibrillar amyloid beta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid beta-related and tau-related pathologies. Mt Sinai J Med 77:17&-31, 2010. (c) 2010 Mount Sinai School of Medicine