Examining the Role of Arginase1 Overexpression in an Animal Model of Tauopathy
Poster Feb 13, 2017
Shannon Varughese, Andrii Kovalenko, Kevin Ratnasamy, Jerry Hunt Jr, Sarah N. Fontaine, PhD, Leslie A. Sandusky, PhD, Chad Dickey, PhD, Daniel C. Lee, PhD
Alzheimer’s disease (AD) is a neurodegenerative disorder that is becoming increasingly widespread worldwide. This debilitating disease is characterized by neurofibrillary tangles and plaques in the brain composed of tau and amyloid beta peptide plaques, respectively. One of the leading causes of plaques and tangles is the hyperphosphorylation of tau, which is associated with cognitive impairment and decline in memory processes.
It has been found that polyamines may have a neuroprotective role and are currently being investigated further. An essential pathway that leads to production of polyamines is the L-arginine pathway. Metabolism of L-arginine can go two ways; metabolism via arginase produces polyamines and other essential molecules. Metabolism via nitric oxide synthase produces nitric oxide and other harmful molecules that contribute to nitric oxide stress. Because of the possible beneficial role of polyamines, metabolism of arginine by arginase is of interest. Recently, our lab has recently shown that arginase1 overexpression has the ability to reduce phosphorylated tau and neurofibrillary tangles in rTg4510 and PS19 tau transgenic mice. Based on these data, we utilized the transgenic tetO MAPT*P301L mouse model to examine a potential therapeutic gene of interest, arginase1, in an animal model of tauopathy. The model used in this study is unique, in that the administration of the viral-mediated gene therapy (adeno-associated virus serotype 9; AAV9) not only activates the mouse transgene (under a tetracycline activator protein (tTa2) promoter), but also the viral tandem gene with the viral construct. In doing so, we were able to effectively deliver treatments to regions that are concurrently expressing tau neuropathology: regionally in the hippocampus rather than global expression. The design of this study involves six different groups: (1) non-transgenic given AAV9-Empty Capsid, (2) non-transgenic given AAV9-tTA-GFP, (3) non-transgenic given AAV9-tTA-ARG1, (4) tetO MAPT*P301L mice given AAV9-Empty Capsid, (5) tetO MAPT*P301L given AAV9-tTA-GFP, and (6) tetO MAPT*P301L given AAV9-tTA-ARG1. All mice were injected bilaterally in the hippocampus and allowed to incubate for a period of 14-weeks before tissue collection. This study examined whether arginase1 overexpression was able to prevent the accumulation of neuropathology in an animal model of tauopathy using western blot. These data identify arginase1 as a potential therapeutic for the treatment of tauopathy and neuropathology.
Assessment of Oral LISPRO Treatment in Ameliorating Amyloid and Tau Pathology in Transgenic Alzheimer’s Mice ModelPoster
Ionic co-crystals of lithium salicylate with organic proline (LISPRO) showed better safety and pharmacokinetic profile of lithium in plasma and brain of wild-type and transgenic Alzheimer mice model compared to lithium salts.READ MORE
CiPA Phase 2 Study: validation of an automated microelectrode array (MEA) assay of hiPSC-derived cardiomyocyte electrophysiology for cardiac safety evaluationPoster
These results support the use of hSC-CM and MEA technology for preclinical assessment of proarrhythmic risk within the proposed CiPA paradigm, and, more generally, demonstrate that automation of the CM-MEA assay can achieve high reliability and throughput for cardiac risk assessment in vitro.READ MORE
Modulation of GPRC6A Signaling to Mitigate TauopathiesPoster
Overall, our data suggest that decreased GPRC6A signaling reduces tau pathology. Further studies is required to warrant the role of GPRC6A in amino acid sensing associated autophagy or other protein degradation mechanisms. GPRC6A allosteric antagonists may potentially find utility as novel drugs to treat tauopathies and related disorders.READ MORE