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P1–063: Deregulation of NMDA–receptor function and signaling in APP[V717O] transgenic mice
Author(s) -
Dewachter Ilse,
Burckhardt C.,
Filipkowski R.,
Neyton J.,
Ris L.,
Borghgraef P.,
Croes S.,
Godaux E.,
Kaczmarek L.,
Herms J.,
Van Leuven F.
Publication year - 2006
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.2006.05.438
Subject(s) - nmda receptor , long term potentiation , long term depression , synaptic plasticity , neuroscience , hippocampal formation , microbiology and biotechnology , biology , receptor , genetically modified mouse , chemistry , transgene , ampa receptor , biochemistry , gene
tau isoform htau46 (2 3-10 ), which is one of the major tau isoforms in human brain. The construct was mutated at sites G272V and P301S and is expressed under a thy1-promotor. Results: This novel tau model displays AD-like tau pathology in the absence of any motor dysfunction. The transgene is found in high concentrations in cortex, hippocampus and amygdala but only traces in the spinal cord. THY-Tau22 shows hyperphosphorylation of tau on several AD-relevant tau epitopes (AT8, AT100, AT180, AT270, tau-pSer396 and tau-pSer422) and neurofibrillary tanglelike inclusions (Gallyas and MC1-positive) starting from 3-6 months of age accompanied by a mild astrogliosis. In addition activated microglia accumulates in the near vicinity to phospho-tau. These mice also display deficits in hippocampal basal synaptic transmission at 14 months while long term potentition (LTP) is not affected at 3 and 14 months indicating a loss of functional synapses. These pathophysiological observations are associated with an impaired behavior characterized by an increased anxiety at 6 months, delayed learning from 3 months and reduced spatial memory at 10 months. There are no signs of motor deficits or any changes in motor activity over all ages investigated. Conclusions: This mouse model displays the main features of tau pathology and several of the pathophysiological disturbances observed in AD and it is the first tau mouse model without displaying any motor deficits. It will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits in AD during pathogenic tau aggregation.