title: Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease.
abstract: Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aβ. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aβ and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Aβ-plaques and synapse loss, with rTg21221 mice, which overexpress wild-type human tau. When compared to the APP/PS1 mice without human tau, the cross-sectional area of ThioS+ dense core plaques was increased by ~50%. Along with increased plaque size, we observed an increase in plaque-associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Aβ at synapses. Together, these results indicate that adding human wild-type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque-associated synapse loss.
authors.affiliation: Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Jackson
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Rudinskiy
authors.affiliation: Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Herrmann
authors.affiliation: Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Croft
authors.affiliation: Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: JeeSoo Monica
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: Veselina
authors.initials: V
authors.lastname: Petrova
authors.affiliation: University of Cadiz, Cadiz, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Ramos-Rodriguez
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wegmann
authors.affiliation: University of Cadiz, Cadiz, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia-Alloza
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; D053764:Presenilin-1; C580804:presenilin 1, mouse; D016875:tau Proteins
keywords: Alzheimer; amyloid beta; plaque; synapse; tau