Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits.
Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation.
Schindowski
Katharina
K
INSERM U815, Place de Verdun, 59045 Lille Cedex, France. katharina.schindowski@lille.inserm.fr
Bretteville
Alexis
A
Leroy
Karelle
K
Bégard
Séverine
S
Brion
Jean-Pierre
JP
Hamdane
Malika
M
Buée
Luc
L
D000375:Aging; D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008569:Memory Disorders / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019957:Motor Skills Disorders / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration; D016874:Neurofibrillary Tangles / Q000648:ultrastructure; D010766:Phosphorylation; D011487:Protein Conformation; D013569:Synapses / Q000473:pathology*; D009435:Synaptic Transmission / Q000502:physiology; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D016875:tau Proteins