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P1‐081: Memantine reduces amyloid and Tau pathologies in a triple‐transgenic mouse model of Alzheimer's disease
Author(s) -
Green Kim N.,
Martinez-Coria Hilda,
Banerjee Pradeep K.,
Gupta Sandeep,
LaFerla Frank M.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.667
Subject(s) - memantine , nmda receptor , genetically modified mouse , pharmacology , alzheimer's disease , tau protein , medicine , psychology , transgene , neuroscience , chemistry , disease , receptor , biochemistry , gene
disease states. Cortical neurons cultured from ASK1 knock-out (KO) mice are claimed to show attenuated neuronal cell death following incubation with A 25-35 peptide, suggesting a role in Alzheimer’s disease. ASK1 is reported also to be activated in in vitro and in vivo models of Parkinson’s disease. Introduction of a point mutation has allowed us to generate an ASK1 kinase dead knock-in (KI) mouse model which more accurately mimics the effects of a small molecule inhibitor, i.e. the presence of a kinase-inactive ASK1 protein. Methods: ASK1 mice were generated containing as point mutation in the kinase active site (K716R). For in vitro analysis, cortical neurons were isolated from E15 embryos, cells treated with A 1-42 peptide and toxicity measured using an LDH assay. Animals were treated with 10-30mg/kg MPTP and beam walking behaviour assessed. Striatal catecholamine content was measured using HPLC 7 days following MPTP treatment. Results: Signalling via ASK1 was reduced in astrocytes from ASK1 KI mice, as evidenced by a reduction in p38 activation following either an H2O2 or LPS stimulus. However, primary cortical neurons cultured from either ASK1 KI or wild-type mice displayed similar extents of cell death when incubated with A 1-42 peptide. Our results thus demonstrate a clear difference in cellular responses between cells taken from ASK1 KO compared to those from the ASK1 KI mice. ASK1 KI mice treated with MPTP showed significantly reduced behavioural deficits compared to wild-type animals. In addition, MPTP induced reductions in striatal catecholamine content were attenuated in ASK1 KI mice compared to wild type control mice, suggesting a neuroprotective phenotype. Conclusions: In conclusion our results show that cells from ASK1 KI mice display biochemical differences from wild-type cells, as a function of cell type and stimulus, together with a reduced phenotype when challenged in vivo with an oxidative stress agent commonly used as in model of Parkinson’s disease.