title: Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer's disease.
abstract: Synaptic dysfunction and loss is the strongest pathological correlate of cognitive decline in Alzheimer's disease (AD) with increasing evidence implicating neuropathological tau protein in this process. Despite the knowledge that tau spreads through defined synaptic circuits, it is currently unknown whether synapse loss occurs before the accumulation of tau or as a consequence. To address this, we have used array tomography to examine an rTgTauEC mouse model expressing a P301L human tau transgene and a transgene labeling cytoplasm red (tdTomato) and presynaptic terminals green (Synaptophysin-EGFP). All transgenes are restricted primarily to the entorhinal cortex using the neuropsin promotor to drive tTA expression. It has previously been shown that rTgTauEC mice exhibit neuronal loss in the entorhinal cortex and synapse density loss in the middle molecular layer (MML) of the dentate gyrus at 24 months of age. Here, we observed the density of tau-expressing and total presynapses, and the spread of tau into the postsynapse in the MML of 3-6, 9, and 18 month old red-green-rTgTauEC mice. We observe no loss of synapse density in the MML up to 18 months even in axons expressing tau. Despite the maintenance of synapse density, we see spread of human tau from presynaptic terminals to postsynaptic compartments in the MML at very early ages, indicating that the spread of tau through neural circuits is not due to the degeneration of axon terminals and is an early feature of the disease process.
authors.affiliation: The University of Edinburgh Centre for Cognitive and Neural Systems, Centre for Dementia Prevention and the Euan MacDonald Centre for Motor Neurone Disease Research, 1 George Square, Edinburgh, United Kingdom.
authors.forename: Eleanor K
authors.initials: EK
authors.lastname: Pickett
authors.affiliation: The University of Edinburgh Centre for Cognitive and Neural Systems, Centre for Dementia Prevention and the Euan MacDonald Centre for Motor Neurone Disease Research, 1 George Square, Edinburgh, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Henstridge
authors.affiliation: The University of Edinburgh Centre for Cognitive and Neural Systems, Centre for Dementia Prevention and the Euan MacDonald Centre for Motor Neurone Disease Research, 1 George Square, Edinburgh, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Allison
authors.affiliation: McLaughlin Research Institute, Great Falls, Montana.
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts.
authors.forename: Amy
authors.initials: A
authors.lastname: Pooler
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wegmann
authors.affiliation: McLaughlin Research Institute, Great Falls, Montana.
authors.forename: George
authors.initials: G
authors.lastname: Carlson
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: The University of Edinburgh Centre for Cognitive and Neural Systems, Centre for Dementia Prevention and the Euan MacDonald Centre for Motor Neurone Disease Research, 1 George Square, Edinburgh, United Kingdom.
authors.forename: Tara L
authors.identifier: 0000-0003-2530-0598
authors.initials: TL
authors.lastname: Spires-Jones
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D018728:Entorhinal Cortex / Q000378:metabolism / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins
keywords: Alzheimer's disease; array tomography; rTgTauEC; tau