Chaperone-mediated modulation of tau aggregation correlates with modifications in tau pathology and synaptic plasticity

Chaperone-mediated modulation of tau aggregation correlates with modifications in tau pathology and synaptic plasticity

Poster Presentations P3 P3-423 LIRAGLUTIDE, A NOVEL DRUG TO TREAT TYPE 2 DIABETES, PREVENTS THE IMPAIRMENT OF LEARNING AND HIPPOCAMPAL SYNAPTIC PLAST...

45KB Sizes 0 Downloads 13 Views

Poster Presentations P3 P3-423

LIRAGLUTIDE, A NOVEL DRUG TO TREAT TYPE 2 DIABETES, PREVENTS THE IMPAIRMENT OF LEARNING AND HIPPOCAMPAL SYNAPTIC PLASTICITY IN AN APP/PS-1 MOUSE MODEL OF ALZHEIMER’S DISEASE

Christian Holscher, Vadivel Parthsarathy, Victor A. Gault, Paula L. McClean, Ulster University, Coleraine, United Kingdom. Contact e-mail: [email protected] Background: Recent research has shown that type 2 diabetes is a risk factor for Alzheimer’s disease. In type 2 diabetes, insulin signalling is impaired. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting analogues such as liraglutide (VictozaÒ) are on the market as treatment for diabetes. GLP-1 also has neuroprotective properties and acts as a growth factor in the brain. We have previously shown that liraglutide crosses the blood-brain barrier and increases synaptic plasticity (LTP) in the hippocampus. We tested Liraglutide in an Alzheimer mouse model (APP/PS1 DeltaE9) in chronic ip. injection to test whether memory impairments and the reduction of LTP in the hippocampus in this AD model can be prevented. Plaques formation and stem cell activation in the brain was also analysed. Methods: Liraglutide was injected for 4 weeks at 200mg/kg bw ip .once daily in wild type or APP/PS1 mice. Learning ability of animals was analysed in an object recognition task and a water maze task. Evoked fEPSPs were recorded in vivo in the hippocampus area CA1. LTP was induced by standard HFS protocols. A wild-type group was also injected with the GLP-1 antagonist exendin(9-36) at 25nmol/kg ip. once daily. Histology was performed to analyse plaque load in the tg mice, and the activation of neuronal progenitor cells in wt mice brains (BrdU stain). Data were analysed by 2-way or 1-way ANOVA with post-hoc tests. Results: Liraglutide prevented the age-dependent impairment of APP/PS1 mice in spatial learning in the water maze task (p < 0.001). Furthermore, age-dependent decay of LTP in the hippocampus was rescued by the drug (p < 0001). In wild type mice, exendin(9-36) impaired learning an object recognition task (p < 0.01) and a water maze task (p < 0.01). LTP was enhanced by liraglutide (p < 0.001) and impaired by exendin(9-36) (p < 0.01). Neuronal progenitor cells count in the dentate gyrus was greatly increased by liraglutide (p < 0.01) and reduced by exendin(9-36) (p < 0.005). The plaque analysis is currently ongoing. Conclusions: The results show that liraglutide has neuroprotective properties even when injected peripherally. Liraglutide is currently prescribed to diabetics, and our results suggests that it might also be effective in preventing neurodegenerative processes observed in Alzheimer’s disease. P3-424

SODIUM SELENATE SPECIFICALLY BOOSTS PP2A PHOSPHATASE, DEPHOSPHORYLATES TAU AND REVERSES MEMORY DEFICITS AND PREVENTS NEUROFIBRILLARY TANGLE FORMATION IN ALZHEIMER’S DISEASE MODELS

Christopher M. Hovens1, Lars M. Ittner2, Daniel Martin1, Birgit HutterPaier3, Manfred Windisch3, Anne Nguyen1, Anthony J. Costello1, Jurgen Gotz4, Niall M. Corcoran1, 1University of Melbourne, Parkville, Australia; 2Brain and Mind Research Institute University of Sydney, Sydney, Australia; 3JSW CNS Research, Forschungslabor GmbH, Graz, Austria; 4 Brain and Mind Research Institute, University of Sydney, Sydney, Australia. Contact e-mail: [email protected] Background: The role of tau protein hyperphosphorylation and subsequent aggregation in the aetiology of Alzheimer’s disease has attracted growing attention of late. However, compared to agents that interfere with b-amyloid deposition, little has been done to identify druggable candidates that would act to reduce tau protein phosphorylation and/or levels. Tau protein phosphorylation could theoretically, either be reduced by inhibiting the key kinase/s responsible for the Alzheimer’s signature phospho-tau epitopes or by boosting the activity of the key phosphatase/s which mediate dephosphorylation of those same phospho-epitopes. One of the key phosphatases impli-

S577

cated in regulating tau protein phosphorylation is the serine-threonine phosphatase PP2A. PP2A is found colocalized with tau and microtubules in the brain and is the most active phosphatase in mediating dephosphorylation of abnormal phospho-tau. Methods: Transgenic TAU441mice, over-expressing human mutant FTDP-17 TAU under the control of the brain specific murine Thy-1 promoter were treated with sodium selenate for 3 months from 5 months of age. Transgenic P301L mice (8 months age) were treated with sodium selenate for 4 months. Immunohistochemistry, neuropathology and a range of behavioural tests were performed on treated animals including Open Field Test, Rota Rod Test, Nose Poke Curiosity Test and Morris Water Maze (MWM). Results: We conducted an in vitro reductive screen and determined that sodium selenate acted as a specific agonist for PP2A, significantly boosting phosphatase activity. Acute treatment of normal aged mice with sodium selenate reduced tau protein phosphorylation in the CNS. Sodium selenate treated transgenic TAU441 mice had significantly lower levels of phospho and total tau levels in the hippocampus and amygdala compared with transgenic non-treated littermates. Sodium selenate treated TAU441 mice exhibited significantly improved spatial learning and memory on the Morris water maze compared with vehicle control transgenic mice. P301L transgenic mice treated with sodium selenate exhibited significantly less NFTs on Gallyas staining of amygdala sections than vehicle treated control mice. Conclusions: Sodium selenate is a specific activator of PP2A with excellent oral bioavailablity, and favourable CNS penetrating properties. A Phase IIa clinical biomarker study in early stage AD patients will commence in 2010. P3-425

CHAPERONE-MEDIATED MODULATION OF TAU AGGREGATION CORRELATES WITH MODIFICATIONS IN TAU PATHOLOGY AND SYNAPTIC PLASTICITY

Jose F. Abisambra1, Laura J. Blair1, Jeffrey R. Jones1, Clara Kraft1, Shannon Hill2, Justin Rogers1, John Koren, III,1, Umesh K. Jinwal1, Lisa Lawson1, Amelia G. Johnson1, Karen Jansen-West3, Martin Muschol2, Jessica Banko1, Todd Golde3, Edwin J. Weeber1, Chad A. Dickey1, 1University of South Florida Alzheimer’s Institute, Tampa, FL, USA; 2University of South Florida, Tampa, FL, USA; 3Mayo Clinic Jacksonville, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: Molecular chaperones play an important role in regulating the aggregation of a number of proteins, such as the microtubule stabilizer tau, that pathologically accumulate in neurodegenerative diseases. Identifying ways to manipulate these toxic processes is an area of intense investigation; however, the translation of these results to the mammalian brain has progressed more slowly. Methods: We optimized and implemented extrinsic genetic delivery of molecular chaperones using adeno-associated viral (AAV) particles to transgenic mice that develop tau pathology. We used confocal microscopy and rigorous image analysis to quantify neuronal tau, the results of which were further correlated with modifications in long-term potentiation (LTP). To measure changes in tau aggregation in the presence of chaperones, we performed in vitro experiments such as atomic force microscopy, dynamic light scattering, sucrose-cushioned western blots, and a novel technique coupling Ponceau S-dot blots with near-infrared protein visualization. Finally, we identified several other tau-modulating chaperones by screens consisting of plasmid and siRNA transfection of cell culture models. Results: We show for the first time that the transgenic model of tauopathy evaluated has deficits in hippocampal plasticity. This feature was rescued to normal levels with AAV-delivery of chaperones like Hsp27. This result paralleled clearance of tau pathology via heat-shock protein over-expression. In vitro evaluation of tau-chaperone interactions revealed critical mechanistic steps regulating chaperone expression and activation, which are necessary for the abovementioned results. Conclusions: Genetic manipulation of Hsps is an effective means to modify tau aggregation in vivo and in vitro, which in turn may translate into improved hippocampal plasticity. Therefore, further efforts to pharmacologically control Hsp expression and activation may serve as potential therapeutics for tauopathies and other diseases where misfolded protein aggregation is a pathological culprit.