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P2‐383: Reversal of spatial problem‐solving cognitive deficit in a transgenic mouse line overexpressing the repeat domain of Tau by treatment with the Tau aggregation inhibitor methylthioninium chloride
Author(s) -
Melis Valeria,
Deiana Serena,
Zabke Claudia,
Stamer Karsten,
Harrington Charles R.,
Riedel Gernot,
Theuring Franz,
Seng Kwang Meng,
Wischik Claude 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.2008.05.1461
Subject(s) - genetically modified mouse , transgene , neocortex , morris water navigation task , cognition , neuroprotection , neuroscience , medicine , psychology , chemistry , biology , biochemistry , gene
ylated at several disease-relevant epitopes, leading to progressive neuronal dystrophy and formation of RIPA-insoluble tau. AD-like tau hyperphosphorylation was reduced by the tau kinase inhibitors lithium as well as SRN 003-556, but RIPA-insoluble tau accumulated regardless of reduced tau phosphorylation. Moreover, we obtained evidence that synapse pathology, assessed by two markers for synaptic vesicles, preceded axon and cell body degeneration which is in line with previous in vivo observations. Specifically SRN 003-556, a kinase inhibitor that may partially inhibit multiple tau kinases, but not lithium was able to protect hippocampal neurons from synaptic damage that was presumably caused by a toxic soluble tau fraction. Synapse protection correlated with reduced neurodegeneration observed at later stages. Conclusions: These data provide first mechanistic insights towards the functional benefits of tau kinase inhibition that have been observed in vivo. The ex vivo model system of hippocampal tau pathology described here may facilitate the identification of drug candidates, in particular kinase inhibitors, and help to identify modulators of tau toxicity in hippocampal neurons.