Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model.
Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old P301S Tg mice before fibrillary tau tangles emerged. Prominent microglial activation also preceded tangle formation. Importantly, immunosuppression of young P301S Tg mice with FK506 attenuated tau pathology and increased lifespan, thereby linking neuroinflammation to early progression of tauopathies. Thus, hippocampal synaptic pathology and microgliosis may be the earliest manifestations of neurodegenerative tauopathies, and abrogation of tau-induced microglial activation could retard progression of these disorders.
Yoshiyama
Yasumasa
Y
The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Higuchi
Makoto
M
Zhang
Bin
B
Huang
Shu-Ming
SM
Iwata
Nobuhisa
N
Saido
Takaomi C
TC
Maeda
Jun
J
Suhara
Tetsuya
T
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000375:Aging / Q000502:physiology; D000679:Amygdala / Q000473:pathology; D017772:Amyloid Neuropathies / Q000473:pathology; D000818:Animals; D001284:Atrophy; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D005911:Gliosis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008262:Macrophage Activation / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000502:physiology*; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism; D019599:Mossy Fibers, Hippocampal / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000473:pathology* / Q000502:physiology; D010766:Phosphorylation; D012995:Solubility; D013116:Spinal Cord / Q000473:pathology; D013569:Synapses / Q000473:pathology*; D016559:Tacrolimus / Q000627:therapeutic use; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics*
D007166:Immunosuppressive Agents; D016875:tau Proteins; D016559:Tacrolimus