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Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease.
Eur J Neurosci. 2016 12; 44(12):3056-3066.EJ

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.

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Authors+Show Affiliations

Jackson RJ
Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Rudinskiy N
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Herrmann AG
Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Croft S
Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Kim JM
Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Petrova V
Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Ramos-Rodriguez JJ
University of Cadiz, Cadiz, Spain.
Pitstick R
McLaughlin Research Institute, Great Falls, MT, USA.
Wegmann S
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Garcia-Alloza M
University of Cadiz, Cadiz, Spain.
Carlson GA
McLaughlin Research Institute, Great Falls, MT, USA.
Hyman BT
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Spires-Jones TL
Centre for Cognitive and Neural Systems and Centre for Dementia Prevention, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsAstrocytesDisease Models, AnimalHumansMiceMice, TransgenicNeuronsPhosphorylationPlaque, AmyloidPresenilin-1Synapsestau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27748574

Citation

Jackson, Rosemary J., et al. "Human Tau Increases Amyloid Β Plaque Size but Not Amyloid Β-mediated Synapse Loss in a Novel Mouse Model of Alzheimer's Disease." The European Journal of Neuroscience, vol. 44, no. 12, 2016, pp. 3056-3066.
Jackson RJ, Rudinskiy N, Herrmann AG, et al. Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease. Eur J Neurosci. 2016;44(12):3056-3066.
Jackson, R. J., Rudinskiy, N., Herrmann, A. G., Croft, S., Kim, J. M., Petrova, V., Ramos-Rodriguez, J. J., Pitstick, R., Wegmann, S., Garcia-Alloza, M., Carlson, G. A., Hyman, B. T., & Spires-Jones, T. L. (2016). Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease. The European Journal of Neuroscience, 44(12), 3056-3066. https://doi.org/10.1111/ejn.13442
Jackson RJ, et al. Human Tau Increases Amyloid Β Plaque Size but Not Amyloid Β-mediated Synapse Loss in a Novel Mouse Model of Alzheimer's Disease. Eur J Neurosci. 2016;44(12):3056-3066. PubMed PMID: 27748574.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease. AU - Jackson,Rosemary J, AU - Rudinskiy,Nikita, AU - Herrmann,Abigail G, AU - Croft,Shaun, AU - Kim,JeeSoo Monica, AU - Petrova,Veselina, AU - Ramos-Rodriguez,Juan Jose, AU - Pitstick,Rose, AU - Wegmann,Susanne, AU - Garcia-Alloza,Monica, AU - Carlson,George A, AU - Hyman,Bradley T, AU - Spires-Jones,Tara L, Y1 - 2016/11/12/ PY - 2016/07/11/received PY - 2016/09/21/revised PY - 2016/10/13/accepted PY - 2016/10/18/pubmed PY - 2017/11/14/medline PY - 2016/10/18/entrez KW - Alzheimer KW - amyloid beta KW - plaque KW - synapse KW - tau SP - 3056 EP - 3066 JF - The European journal of neuroscience JO - Eur J Neurosci VL - 44 IS - 12 N2 - 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. SN - 1460-9568 UR - https://www.unboundmedicine.com/medline/citation/27748574/Human_tau_increases_amyloid_β_plaque_size_but_not_amyloid_β_mediated_synapse_loss_in_a_novel_mouse_model_of_Alzheimer's_disease_ DB - PRIME DP - Unbound Medicine ER -