title: Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model.
abstract: 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.
authors.affiliation: The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Yoshiyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: 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*
chemical_list: D007166:Immunosuppressive Agents; D016875:tau Proteins; D016559:Tacrolimus