title: Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer's disease.
abstract: The accumulation of neurofibrillary tangles in Alzheimer's disease (AD) propagates with characteristic spatiotemporal patterns which follow brain network connections, implying trans-synaptic transmission of tauopathy. Since misfolded tau has been shown to transmit across synapses in AD animal models, we hypothesized that synapses in AD patients may contain misfolded tau. By immunofluorescence imaging of bipartite synapses from AD subjects, we detected tau protein in 38.4% of presynaptic and 50.9% of postsynaptic terminals. The pre/post distribution for hyperphosphorylated tau was 26.9%/30.7%, and for misfolded tau 18.3%/19.3%. In the temporal cortex, microscopic aggregates of tau, containing ultra-stable oligomers, were estimated to accumulate within trillions of synapses, outnumbering macroscopic tau aggregates such as tangles by 10000 fold. Non-demented elderly also showed considerable synaptic tau hyperphosphorylation and some misfolding, implicating the synapse as one of the first subcellular compartments affected by tauopathy. Misfolding of tau protein appeared to occur in situ inside synaptic terminals, without mislocalizing or mistrafficking. Misfolded tau at synapses may represent early signs of neuronal degeneration, mediators of synaptotoxicity, and anatomical substrates for transmitting tauopathy, but its actual role in these processes remain to be elucidated.
authors.affiliation: Department of Chemistry, National Taiwan University, 1 Roosevelt Road Section 4, Taipei, 106, Taiwan. hctai@ntu.edu.tw.
authors.forename: Hwan-Ching
authors.initials: HC
authors.lastname: Tai
authors.affiliation: Department of Chemistry, National Taiwan University, 1 Roosevelt Road Section 4, Taipei, 106, Taiwan. r01223211@ntu.edu.tw.
authors.forename: Bo Y
authors.initials: BY
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Iowa Hospitals & Clinics, Iowa City, IA, USA. Alberto-serranopozo@uiowa.edu.
authors.forename: Alberto
authors.initials: A
authors.lastname: Serrano-Pozo
authors.affiliation: C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. matthew_frosch@hms.harvard.edu.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Centre for Cognitive and Neural Systems and the Euan MacDonald Centre for Motor Neurone Disease, University of Edinburgh, Edinburgh, UK. tspires@staffmail.ed.ac.uk.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Building 114, 16th Street, Charlestown, MA, 02129, USA. bhyman@mgh.harvard.edu.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D046169:Dermoscopy; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008297:Male; D061848:Optical Imaging / Q000379:methods; D010766:Phosphorylation; D017510:Protein Folding; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins