NYU Langone Investigators to Present New Research at 2014 Alzheimer's Association International Conference in Copenhagen, Denmark
Reporters Tip Sheet
Embargo expired: 17-Jul-2014 10:00 AM EDT
Source Newsroom: NYU Langone Medical Center
Please Note: All Material is Embargoed Until July 17, 2014, At The End of The Conference or After Being Presented.
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Reporters Tip Sheet
(New York, NY, July 12, 2014) - Researchers from the Center for Cognitive Neurology (CCN) at NYU Langone Medical Center, NYU School of Medicine, and the Nathan S. Kline Research Institute will present new findings at the 2014 Alzheimer's Association International Conference in Copenhagen, Denmark, July 12 – 17, 2014.
The Center for Cognitive Neurology (CCN) is a multidisciplinary, integrated center within NYU Langone, devoted to research, clinical care and clinical advances toward the treatment and cure of neurological diseases affecting cognition -- focused on memory, language, attention, auditory, visual and thinking difficulties. The Center is comprised of the Silberstein Alzheimer's Institute which houses the Alzheimer's Disease Center (ADC) and the Pearl I. Barlow Center for Memory Evaluation and Treatment; and basic, translational and clinical research is conducted within more than 20 major NYU centers, programs and laboratories. The focus is on improving the understanding and treatment of diseases and injuries to the nervous system. Neurologists and neuroscientists conduct research in the risks, predictors, prevention, diagnostic tests and potential treatments for Alzheimer's disease (AD), Lewy Body dementia (LBD), vascular dementia, prion disease, mild cognitive impairment, and other related conditions, and have expertise in evaluating, diagnosing and treating individuals with brain conditions that affect memory and/or thinking (cognition). The Center works closely with the NYU Neuroscience Institute, the NYU Parkinson and Movement Disorders Center, the Center for Brain Health, and the Nathan S. Kline Institute for Psychiatric Research.
The NYU Alzheimer’s Disease Center is one of 29 Alzheimer's disease research centers in the United States supported by the National Institute on Aging (NIA). As an NIA-supported research facility, the center's goals are to advance current knowledge and understanding of brain aging and Alzheimer's disease, to expand the numbers of scientists working in the field of aging and Alzheimer's research, to work toward better treatment options and care for those living with memory impairment, and most importantly, share these findings with healthcare providers, researchers, and the general public to enhance the care of those affected by Alzheimer’s disease and related dementia.
Oral presentations are listed first and Poster presentations second. We will be happy to provide full copies of the presentations, abstract and posters. Our researchers are available for comment and can be reached in Denmark. NYU Langone also has researchers located in the United States who can provide insight into
breaking news from the Alzheimer’s Conference.
Symposium Name: Non-amyloid Based Therapies, 8:30am-10:00 am
S1-02-04 - Sunday, July 13, 2014, 9:30am – 9:50am - Oral Presentation (includes q and a)
Author: Sigurdsson, E.M., PhD
Tau immunotherapy has great potential for Alzheimer’s disease and other tauopathies. Compared to amyloid-β, clearing pathological tau proteins is likely to be effective later in the disease, as the degree of tau pathology correlates better with dementia severity than amyloid-β plaque burden. Both active and passive tau immunizations against various epitopes are effective in mouse models, and one Phase 1 study with a tau immunogen is already underway. Most companies, however, are focused on developing tau antibodies for proof of concept clinical studies. The active approach remains riskier but has excellent future potential, in particular if it can be tailored to the individual’s haplotype to maximize beneficial immune response and minimize adverse reactions.
The efficacy in the mouse studies can be explained by both extra- and intracellular antibody-mediated clearance of tau aggregates. The importance of each pathway may depend on the properties of the antibodies, the stage of the disease and the experimental model. Some of the positive effects of active tau immunotherapy may also in part be related to favorable T-cell responses, which have not been thoroughly studied in this context.
The increased focus in recent years on the tau protein for therapy has renewed interest in it for diagnosis. Beside a few β-sheet dyes that have advanced into clinical trials, antibodies and their derivatives should be considered and are likely to be more specific for pathological tau lesions. We have shown those to reliably enter the brain and identify mice with brain tau pathology in vivo after peripheral injection. The short half-life of the fragments is particularly suitable for imaging. Such targeting may provide valuable information on the tau epitope profile of each patient to tailor therapy for maximal efficacy and safety. Further development of tau antibodies and their derivatives as therapies is likely to advance their use as diagnostic probes as well.
Hopefully, these approaches will be shown to be effective in clinical trials in the near future. Better understanding of the mechanisms involved should lead to improved efficacy of such therapies and enhance the accuracy of related diagnostic agents for tauopathies and other protein aggregation diseases.
Monday, July 14, 2014 at 4:00pm - Oral Presentation – Platform Talk “Mitochondria And Death Receptors: Key Targets For Amyloid Toxicity In The Cerebral Vasculature “
Silvia Fossati, PhD, Research Assistant Professor of Pathology, NYU School of Medicine, Patrizia Giannoni, Mar Hernandez, Joan Montaner, Jorge Ghiso, Agueda Rostagno
Background: The vascular deposition of amyloid, known as Cerebral Amyloid Angiopathy (CAA), is an age-associated condition featured in about 90% of Alzheimer’s disease cases. CAA compromises cerebral blood flow and can cause cerebral hemorrhage and cognitive impairment. Very little is known about the mechanisms initiating the amyloid beta (Abeta)-dependent degeneration of cerebral endothelial cells in CAA. Here, we aim to identify the molecular events underlying the apoptotic cascade generated by Abeta in cerebrovascular cells and to pinpoint new targets for drug discovery. Conclusions: Overall, our data suggests a primary contribution of TRAIL death-receptors and mitochondrial dysfunction in Abeta-induced vascular cell death, unveiling new cellular targets for therapeutic intervention.
O3-14-02 - Tuesday, July 15, 2014, 4:00pm to 5:30pm - Oral Presentation
“Targeting the Shared Pathological Conformers of both Aß and Hyperphosphylated Tau with a Conformationally Selective Monoclonal Antibody”
Thomas Wisniewski1, Eleanor Drummond2, Krystal Herline2, Yanjie Sun2, Fernando Goni2, 1New York University School of Medicine, New York, New York, United States, 2NYU School of Medicine, New York, New York, United States
Background: Currently there is no effective therapy for AD. Immunomodulation stills hold promise but current attempts only address one aspect of the pathology: either amyloid ß (Aß) or the hyperphosphorylated tau (ptau) protein. Furthermore current approaches are not specific for the pathological conformers of either protein. We have developed a novel immunomodulatory approach using a pBri peptide. ABri is a rare form of familial human amyloidosis associated with a missense mutation in a stop codon resulting in the transcription of an intronic sequence, leading to production of a highly amyloidogenic protein with a carboxyl terminus that has no sequence homology to any native human protein. We hypothesized that through conformational mimicry the polymerized Bri peptide (pBri) could induce a conformation selective immune response that will recognize pathological proteins such as oligomeric tau and Aß. We have tested this approach in APP/PS1, 3xTg and TgSwDI AD mouse models and have documented that use of pBri as an immunogen reduces: amyloid plaques, vascular amyloid deposits and neurofibrillary tangles. Using pBri we have developed monoclonal antibodies (mAbs). Currently we are characterizing one such mAb specific for pathological conformers of Aß and tau. Conclusions: We have developed a novel immunization procedure which we have used to produce monoclonal antibodies (mAbs) that recognize multiple pathological proteins, including PrP Res, oligomer A b and ptau. We are characterizing one of these mAbs, TAB1, which gives selective immunolabeling in AD tissue and on Western blots to pathological conformers. We believe that immunotherapy that specifically targets the most toxic, oligomeric forms of Aß and ptau, has a greater chance of success with much less risk of toxicity.
Session Title: Neuroimaging: Imaging Animal Models
O4-02-02 - July 16 2014 from 2:15 pm - 3:45 pm – Oral Presentation
“Tau Antibody Derivatives as Diagnostic Imaging Agents for Tauopathies”
Authors: Krishnaswamy, S., Lin, Y., Rajamohamedsait, W.J., Rajamohamedsait, H.B., Krishnamurthy, P.K., Pedersen, J.T., Stavenhagen, J.B., Sigurdsson, E.M.,
Background: Diagnostic imaging agents targeting amyloid-β (Aβ) in Alzheimer’s disease (AD) are already in clinical use. Such tau probes are needed to monitor AD progression, the efficacy of tau-targeting therapies, and to identify Aβ negative tauopathies. Antibody-derived ligands are likely to provide excellent specificity for detecting tau lesions, and in particular smaller single chain variable antibody fragments (scFv’s) are attractive for in vivo imaging of tau aggregates.
Conclusion: Tau scFv’s are promising as novel diagnostic markers for AD and related tauopathies, and have therapeutic potential as well.
"Clinical Trials III"
Thursday, July 17th, 2014 - 11:30am - 1:00 pm – Oral Presentation
“1 Year Global Outcome of a Comprehensive, Individualized, Person Centered Management (CI‐PCM) Program + Memantine in Advanced AD: A Randomized Controlled Trial”
Authors: Reisberg, B., Boksay, I., Golomb, J., Agarwal, S., Ghimire, S., Shaker, H., Torossian, C., Xu, J., Kenowsky, S.
Background: The worldwide approval of memantine a decade ago, highlighted both treatment possibilities and ongoing treatment needs of persons with moderate to severe AD. Recognizing these needs, we investigated the added value of a Comprehensive, Individualized, Person Centered Management Program (CI‐PCM) in AD persons receiving memantine treatment. Conclusions: At 28 weeks of treatment, a direct comparison of the magnitude of the effect of the CIPCM program on the NYU CIBIC‐Plus global measure indicated a 900% increment over that of memantine treatment alone (2.7 versus 0.3). This absolute effect magnitude of the CI‐PCM vs.memantine alone increases to 3.3 at 52 weeks 11 times the effect of mementine alone at 28 weeks. We conclude that great benefits, perhaps 11 x those of medication, can be achieved with scientific
management in persons with advanced AD.
Saturday, July 12, 2014 - 12:45pm – 2:45pm - Poster
“Tau Antibody Derivatives as Diagnostic Imaging Agents for Tauopathies”
Authors: Krishnaswamy, S., Lin, Y., Rajamohamedsait, W.J., Rajamohamedsait, H.B., Krishnamurthy, P.K., Pedersen, J.T., Stavenhagen, J.B., Sigurdsson, E.M.,
Background: Diagnostic imaging agents targeting amyloid-β (Aβ) in Alzheimer’s disease (AD) are already in clinical use. Such tau probes are needed to monitor AD progression, the efficacy of tau-targeting therapies, and to identify Aβ negative tauopathies. Antibody-derived ligands are likely to provide excellent specificity for detecting tau lesions, and in particular smaller single chain variable antibody fragments (scFv’s) are attractive for in vivo imaging of tau aggregates. Methods: Libraries of scFv’s were generated from tau antibody hybridomas using phage display technology. Numerous phospho-tau (P-Ser396,404) selective scFv’s were identified by ELISA and characterized further by immunoprecipitation, histology and Biacore. Subsequently, the diagnostic imaging utility for tauopathies was assessed for one of the scFv’s and compared to its parent antibody using In Vivo Imaging System (IVIS) for proof of concept prior to PET studies. Results: The scFv’s showed strong selectivity for phospho-tau vs. non-phospho-tau epitope in ELISA, pulled down tau proteins from AD brains, and bound to pathological tau in AD and Pick’s disease brain sections. The potential diagnostic imaging utility of one of these, with the best phospho-tau selectivity on Biacore (1x10-8 M vs. 4x10-3 M for non-phospho-tau), was characterized further by IVIS. Intracarotid or intravenous scFv injection led to a strong IVIS brain signal in transgenic tauopathy mice, that correlated nicely with scFv signal from brain tissue (r=0.97, p<0.0001, n=9), and brain tau pathology (r=0.94, p<0.0001, n=13). Importantly, limited signal was detected in wild-type mice. Similar findings were observed with the parent antibody (r=0.86, p=0.1, n=5 vs. r=0.75, p<0.062, n=11), although its IVIS signal appeared to be less but these differences need to be confirmed by comparing both probes in the same mice. Analyses of brain tissue collected 4-6 h after injection showed a partial to complete co-localization with stained intraneuronal tau aggregates in tg tauopathy mice but not in wt mice for both scFv and its parent antibody. Furthermore, both colocalized with markers of endosomes-autophagosomes-lysosomes, which are known to contain tau aggregates, suggesting that this interaction takes place in these degradation pathways. Conclusion: Tau scFv’s are promising as novel diagnostic markers for AD and related tauopathies, and have therapeutic potential as well.
Sunday, July 13, 2014, 11:45 am - 2:15 pm - Poster
“ Hippocampal Size Predicts Delayed Primacy Performance In Cognitively Intact Elderly Participants”
Authors: Davide Bruno, Michel Grothe, Jay Nierenberg, Stefan Teipel, and Nunzio Pomara
Background: Bruno et al. (2013) showed that delayed recall at the primacy position (first few items on the list) was a predictor of generalized cognitive decline in a group of cognitively-intact participants followed longitudinally; participants with poorer delayed primacy presented a steeper decline. Bruno et al. speculated that the predictive effect of delayed primacy was due to its reliance upon healthy memory consolidation, which is thought to depend upon hippocampal function. In particular, as evidenced by Hermann et al.’s (1996) lesion study in two clinical populations, the left hippocampus plays a key role in the consolidation of primacy information. Methods: To test the hypothesis that the left hippocampus is involved in the consolidation of delayed primacy information in healthy, cognitively-intact individuals, we analyzed data from 28 participants, aged 60 or above and with an MMSE score of at least 28. Serial position performance was measured with the Buschke selective reminding test (BSRT). Hippocampal size was automatically measured via MRI using high-dimensional spatial transformation and a predefined hippocampus mask. We conducted regression analyses with delayed primacy, delayed recency and total delayed recall performance as outcome variables; predictors were age, family history of Alzheimer’s disease (AD), APOE e4 status, sex, level of education, total intracranial volume, and left and right hippocampal size. Results: The size of both the left and right hippocampus was positively correlated with delayed primacy performance, although left hippocampal size was a slightly better predictor of performance. In contrast, hippocampal size did not predict total delayed recall or recency performance. Conclusions: These findings are consistent with the hypothesis that the hippocampus is involved in delayed primacy consolidation. To our knowledge, this is the first time this has been reported in cognitively-intact older individuals, using in-vivo imaging. Our results shed some light on the relationship between delayed primacy performance and generalized cognitive decline. Since delayed primacy consolidation relies on a healthy hippocampus, and the hippocampus is affected early in AD, it is possible that failure to consolidate delayed primacy items might indirectly signal the incipient emergence of the disease.
P1-123 - Sunday, July 13, 2014 - 11:45AM to 2:15PM - Poster
“ Proteomic Analysis Of Archived Alzheimer’s Disease Brain Tissue Using Laser Capture Micro dissection And LC-MS”
Authors: Eleanor Drummond, Beatrix Ueberheide, Thomas Wisniewski 1New York University School of Medicine , New York, New York, United States
Background: Genome-wide association studies (GWAS) have identified novel genes that are associated with increased risk for Alzheimer’s disease (AD), suggesting that a variety of protein pathways are likely to be involved in the development of late onset AD. However, it is not yet known how these pathways participate in the pathogenesis of AD. Therefore the aim of this study was to use an unbiased proteomic approach to examine localized protein changes in the AD brain at different stages of disease progression. Conclusion: The combined use of laser capture micro dissection and LC-MS to characterize proteins in specific brain structures or cell types has great promise for future studies. Future results using this technique will complement those from GWAS studies, potentially identifying protein pathways uniquely expressed or altered in AD. The function of these identified proteins and consequences of expression in AD can then be pursued in further research and could provide novel therapeutic targets.
P2-120 Monday, July 14, 2014, 11:45am – 2:15pm – Poster
“Increased CSF Matrix Metalloproteinase-9(MMP-9) And Reduced White Matter Integrity In Healthy Elderly”
Authors: Nunzio Pomaraa,b, Chelsea Reicherta, Jay Nierenberga,b, Matthew R. Hallidayc, d, Abhay P. Sagare d, Blas Frangioneb, Berislav V. Zlokovic d
a Nathan Kline Institute, NY; b New York University Langone Medical Center, NY , c University of Southern California, CA, d Keck School of Medicine University of Southern California, CA
Background: MMP-9 is s an important factor in ischemic brain insults and its genetic inactivation is protective. Elevated brain and CSF MMP-9 levels have been reported in Alzheimer's disease (AD) and implicated in neuronal death and BBB dysfunction. Interestingly, age-related elevations in CSF MMP-9 are reported in healthy individuals with the APOE ε4 allele, the major genetic risk factor for AD. However, the relationship between MMP-9 and possible subtle brain abnormalities in this population has not been studied. Diffusion Tensor Imaging (DTI)-derived metrics have been found sensitive to subtle brain changes associated with inflammatory markers. Therefore, we employed DTI to examine the relationship between CSF MMP-9 and white matter integrity. Results: MMP-9 was associated with decreased FA (r= -.35, p= .04) and with increased TR (r= +.44, p=.01) , L1 (r=+ .42, p=.01), and LR (r=+ .42, p=.01 which are indicative of greater white matter pathology in the entire group. Although the number of non-e4 carriers was numerically greater than e4 carriers, only e4 carriers showed significant correlations between MMP-9 and the DTI variables. In contrast MMP-9 was not associated with increased white matter hyper intensities (WMHIs). Discussion: Higher CSF MMP-9 levels in healthy elderly, especially e4 carriers, are associated with subtle loss of white matter integrity in the absence of increased of macrovascular lesions such as WMHIs. Future studies should determine whether these MMP-9-associated effects are related to loss of neurons and atrophy, more subtle microstructural white matter abnormalities and BBB breakdown.
Tuesday, July 15, 2014, 11:45 am - 2:15 pm - Poster
“Uptake of Tau Antibodies into PHF Pre-Treated Transfected Human Neuroblastoma Cells Leads To A Decrease In Tau Protein Levels.”
Authors: D.B. Shamir1, Nina Rosenqvist3, Suhail Rasool1, Jan T. Pedersen3, Einar M. Sigurdsson1,2
Departments of 1Physiology and Neuroscience, and 2Psychiatry, New York University School of Medicine, New York, NY 10016, USA. 3H. Lundbeck A/S, DK-2500 Valby, Denmark.
Our laboratory has pioneered targeting pathological tau proteins for clearance with immunotherapies. We have shown that this approach leads to antibody uptake into neurons, clears tau aggregates from the brain and prevents functional impairments, such as cognitive decline, in mouse tauopathy models.
To clarify the mechanism of action of tau antibodies, we are using naïve and transfected (0N4R P301L tau) SHSY5Y human neuroblastoma cells. To mimic a pathological state, we have incubated these cells with paired helical filaments (PHF) enriched from Alzheimer’s disease (AD) brain for 3 days, and subsequently incubated with tau antibody (Ser396/404 epitope) for 1, 4, or 6 days. Incubation was performed at 10% (normal) and 1% (compromising) FBS media conditions. In parallel, these cells were analyzed using our flow cytometry protocol and western blot analysis for antibody and PHF uptake as well as tau protein profile, respectively.
Transfected cells with 1% FBS had more PHF uptake than all other groups at 1, 4, and 6 days (p<0.0001, p=0.0005, and p=0.0003, respectively, n=3). In both controls and sequentially (PHF and tau antibody) treated samples we observed a gradual increase in tau antibody uptake from 1 to 4 days in both cell lines and additional increase from 4 to 6 days in our transfected line. Only at 6 days of tau antibody incubation and in 1% FBS the transfected cells had significantly greater uptake of tau antibody compared to all other groups (26-39%, p= 0.0002, n=3) and a decrease in total tau and phospho Ser199 tau (64%, p=0.0013 and 49%, p=0.0925, respectively, n=3) levels compared to its PHF incubated control.
The compromised transfected cells at 1% FBS and 6 days of antibody incubation show the most promising results as antibody uptake increases and tau levels decrease. Also, PHF seems to have limited effect on antibody uptake, but provides a condition for tau degradation. This neuroblastoma flow cytometry protocol may give us a new high throughput method to better understand the underlying cellular mechanisms and further development of this immunotherapy approach to treat AD and related tauopathies.
P3-415 – Tuesday, July 15th, 2014, 11:45am to 2:15pm - Poster
“Testing of Innate Immunity Stimulation via TLR9 on Cerebral Amyloid Angiopathy use in Non-Human Primates.”
Author BlockHenrieta Scholtzova4, Pramod N Nehete1, Bharti P Nehete1, Andrea Holmes1, Meredith Spadaccia2, Lisa M Sprinzen4, Mohsin Jamal4, Rachel L Sabado2, Lawrence E Williams1, Thomas Wisniewski3, 1ME Keeling Center for Comparative Medicine and Research , Bastrop, Texas, United States,2Mount Sinai Icahn School of Medicine , New York, New York, United States, 3New York University School of Medicine , New York, New York, United States, 4NYU School of Medicine , New York, New York, United States
Background: Considerable effort has been directed toward the development of immunotherapeutic approaches for AD. A potential complication of immunomodulation is the occurrence of cerebral microhemorrhages associated with increased cerebral amyloid angiopathy (CAA). Our initial findings indicate that stimulation of innate immunity with TLR9 agonist CpG ODN is an effective means of reducing CAA without inducing toxicity in AD mouse models. Transgenic models are ideal for initial screening of a potential therapy; however prior to clinical trials it is imperative to also perform studies in models more similar to humans that naturally develop AD related pathology. We advanced our study using the well characterized non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis). Conclusions: Administration of CpG ODN 2006 in young monkeys was effective in inducing immunostimulatory response in the absence of any toxicity. We believe that this type of immunomodulation will lead to reductions in CAA burden correlating with behavioral improvements, without associated microhemorrhages or encephalitis. Our studies represent the first trial of treatment specifically targeting CAA in non-human primates and will provide essential information prior to any clinical use of CpG ODN.
Wednesday, July 16, 2014, 11:45 am - 2:15 pm - Poster
“Tau Antibody-Mediated Prevention Of Seeding Of Tau Pathology And Associated Toxicity”
Authors: Erin E. Congdon, Suhail Rasool, Jiaping Gu, Einar M. Sigurdsson Tau immunotherapy has great potential for Alzheimer’s disease and other tauopathies but the mechanisms of tau clearance are not well known. We recently reported on two novel tau antibodies targeting the 396/404 region, 4E6G7 and 6B2G12, which are primarily taken up by neurons and reduce tau protein pathology in long term brain slice cultures (Gu J et al, JBC 288, 33081, 2013). Further characterization of one of these antibodies, 4E6G7, revealed that antibody uptake into neurons occurs primarily via clathrin-dependent Fcgamma receptor endocytosis, and is a prerequisite for acute tau protein clearance (Congdon EE et al, JBC 288, 35452, 2013).
To test the efficacy of these antibodies to prevent propagation of tau pathology, primary neurons were incubated with 1 or 10 µg/ml of Alzheimer’s derived paired helical filament (PHF) enriched material, with the tau antibodies (1 µg/ml) added concurrently, or 24 h before or after PHF administration. Tau and NeuN levels were then assessed for up to 7 days.
Incubation with 1 mg/ml PHF increased total tau levels by 59% over 72 h (p<0.001), which was accompanied by a shift towards higher molecular weight tau proteins. 4E6G7, added with or 24 h after PHF, prevented this increase in tau protein levels. In contrast, 6B2G12 was not effective under these conditions (69% and 76% increase in tau protein levels, respectively, p>0.001). Ten times higher PHF concentration had toxic effects with 89% loss of NeuN signal over 7 days (p=0.002), associated with 40% decrease in tau levels up to 48 h (p=0.006), after which they steadily increased. 4E6G7 prevented NeuN signal loss when added with or 24 h after PHF, whereas neurons incubated with PHF and 6B2G12 showed NeuN loss comparable to cells treated with PHF alone (77-81%, p=0.01-0.002). Adding the antibodies 24 h before 10 µg/ml of PHF had no effect, presumably because they are not retained in the absence of tau aggregates.
These data show differing efficacy of tau antibodies to reduce intracellular tau and provide protection from exogenous tau. This culture model is useful to identify promising therapeutic antibodies and to clarify their mediated clearance of tau pathology.
P4-372 - Wednesday July 16th, 11:45am to 2:15pm - Poster
“Anti-Conformational Monoclonal Antibody with Selective Preference for PrPRes Strains from Different Animal Species and Humans”
Author BlockFernando Goni3, Frances Prelli3, Eleanor Drummond2, Krystal Herline4, Mithchell Marta3, Yanjie Sun3, Bernardino Francesco Ghetti1, Thomas Wisniewski2, 1Indiana University School of Medicine , Indianapolis, Indiana, United States, 2New York University School of Medicine , New York, New York, United States, 3NYU School of Medicine , New York, New York, United States, 4NYU SoM , New York, New York, United States
Background: Whilst many active and passive immunization approaches have been developed with limited success, for Alzheimer's disease (AD), immunomodulation has been less studied for prion diseases which involve the conversion of cellular PrPC into a toxic and infectious prion PrP Res. Recent studies by our group has demonstrated that active mucosal immunization is a feasible therapeutic approach to prevent transmission and progression in mouse and deer. In the course of producing conformational monoclonal antibodies (mAbs) with different binding capacities for the Aß and hyperphosphorylated Tau pathological conformers; we developed a few clones that showed distinct activity towards PrP Res using ELISA. These mAbs were developed by selecting clones that recognize ß-sheet oligomeric structures. Such mAbs might be potential tools for detecting, diagnosing and treating prionoses. From a few mAbs that by Western blot showed specific binding to monomeric and multimeric prions we selected one (TAP1) for further characterization. Methods: Monoclonal antibodies obtained from our conformational immunization of BALBc mice using a polymerized 13mer Bri peptide (pBri) were tested for reactivity towards different forms of PrP in ELISA. Selected TAP1 was further characterized by Western blots, ELISAs, immunohistochemistry using human GSS tissue, and potential inhibition of in vitro 22L prion infection of N2a cells. Results: TAP1 reacted strongly in ELISA against different PrP Res preparations. By Western blot it detected oligomeric forms of prions after PK digestion, including samples from human CJD. Using immunofluorescence we detected specific immune labeling of neurons from human GSS cases. TAP1 was also able to significantly reduce infection of N2a cells by 22L prions. Conclusions: We characterized a monoclonal antibody that not only detects AD related pathology but strongly reacted with different oligomeric forms of PrP Res. This type of mAb can be of use for the detection of different prion forms, contributing to the diagnosis, monitoring of disease progress and potential therapy for prion diseases.
Wednesday, July 16 2014 from 11:45 am - 2:15 pm - Poster
“Monitoring Tau Pathology And Monoclonal Antibodies In Vivo By Two-Photon Imaging”
Authors: Lin,Y., Gu,J., Rajamohamedsait,H.B., Rajamohamedsait,W.J., Sigurdsson, E.M.
Background: Studies from our laboratory and more recently several others have demonstrated the efficaciousness of tau immunotherapy. We have developed a monoclonal antibody, 4E6G7, targeting the pSer-396/404 tau epitope. It has been shown to enter neurons and reduce hyperphosphorylated tau in ex vivo brain slice cultures, as well as clear tau aggregates and improve cognition in vivo. Additionally, the specific uptake of 4E6G7 by neurons with tau pathology is dependent on its Fc region. Here, using in vivo two-photon imaging, we investigated the uptake and dynamics of 4E6G7 in live transgenic tauopathy mice. Conclusions: By two-photon imaging of live transgenic mice, we confirmed the ability of tau antibodies to enter brain tissue and specifically bind to tau aggregates. The Fc region of the antibody was required for selectively targeting intraneuronal tau pathology. Decrease in FSB signal over time suggests that tau aggregates may be cleared but requires confirmation with more detailed analyses.
P4-092 - Wednesday, July 16th, 11:45am - 2:15pm - Poster
“Sleep Disordered Breathing in the Elderly and Risk for Alzheimer’s disease using FDG-PET”
Authors: Tyler Gumb, Janna Mantua, Yi Li, Ricardo Osorio
Background: Sleep Disordered Breathing (SDB) is very common in the elderly (30-80%). SDB and Alzheimer’s disease (AD) share a number of risk factors and there is an increased prevalence of SDB in AD patients. Additionally, treating SDB has been shown to improve cognition in AD patients. Elevated AD-risk indicated by CSF biomarkers has been demonstrated in normal elderly with SDB, however AD-risk indicated by FDG PET is unknown. Conclusions: Our observations suggest an association between SDB and preclinical-AD in cognitively normal elderly. Because both AHI 4% and AHIall showed strong associations in our data, we are unable to determine if intermittent hypoxia or sleep fragmentation is more influential on the glucose hypometabolism observed. Additionally, the causal relationships and directionality are unclear from our data. If SDB increases the risk for preclinical AD, this would suggest existing therapies for SDB such as continuous positive airway pressure (CPAP) could be implemented to delay the onset to MCI or dementia in elderly individuals with SDB.
P4-205 - Wednesday July 16th, 11:45am to 2:15pm - Poster
“Mucosal Immunization to Prevent Chronic Wasting Disease (CWD) in Deer”
Fernando Goni3, Candace Mathiason1, Krystal Herline3, Jeanette Hayes-Klug1, Amy Nalls1, Kelly Anderson1, Veronica Estevez5, Lucia Yim6, David Brown4, Jose Alejandro Chabalgoity5, Edward Hoover1, Thomas Wisniewski2, 1Colorado State University , Fort Collins, Colorado, United States, 2New York University School of Medicine , New York, New York, United States, 3NYU School of Medicine , New York, New York, United States, 4University of Bath , Bath, United Kingdom, 5University of Uruguay , Montevideo, Colorado, Uruguay, 6University of Uruguay , Montevideo, Connecticut, Uruguay
Background: Prionoses are transmissible, neurodegenerative disorders. Bovine spongioform encephalopathy (BSE) has crossed the species barrier to infect humans. Chronic wasting disease (CWD) infects large numbers of deer and elk, with the potential to infect humans. Currently no prionosis has an effective treatment. Previously, we have demonstrated we could prevent transmission of prions in a proportion of susceptible mice with a mucosal vaccine. Recently, we have attempted to produce an immune response in animals naturally susceptible to CWD, white tail deer, which could inhibit transmission. Results: All vaccinated animals produced anti-PrP IgA and IgG antibody titers of varying levels. As expected, both vaccinated and control deer produced high titers of IgA and IgG against Salmonella. Three years post CWD oral challenge all control deer developed clinical CWD (median survival 602 days), while among the vaccinated there was a prolongation of the incubation period and one deer remains CWD free clinically and by RAMALT and tonsillar biopsies (p=0.012 by Weibull regression analysis). This negative vaccinate has the highest titers of IgA in saliva and IgG systemic against PrP. Western blots showed that immunoglobulins from this vaccinate react to PrP CWD. Conclusions: Oral immunization can be used to overcome tolerance to self-PrP protein and produce a mucosal IgA and systemic IgG response to normal and conformational modified PrP in large mammals. We document the first partially successful vaccination for a prion disease in a species naturally at risk.
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