title: Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease.
abstract: There is pivotal evidence that tau pathology can be triggered by amyloid-β (Aβ) pathology in experimental systems. On the other side, studies on human brain specimen have elucidated that tau pathology may occur before amyloid pathology is present indicating that in principle tau pathology could also trigger Aβ aggregation. To address this question, we have crossed 5XFAD mice coexpressing human mutant APP695 with the Swedish, Florida, and London mutations and human mutant presenilin-1 (PS1) with the M146L and L286V mutations with the PS19 model overexpressing human mutant tau with the P301S mutation. The resulting triple transgenic model 5XFAD/PS19 has been characterized at 3 and 9 months of age. A dramatic aggravation of hyperphosphorylated tau pathology together with a dramatically increased inflammatory response and a loss of synapses and hippocampal CA1 neurons in aged 5XFAD/PS19 mice were observed. Extracellular amyloid deposits were unaltered. These data support the assumption of tau pathology being downstream of amyloid pathology, suggesting that both pathologies together trigger the severe neuron loss in the hippocampus in the 5XFAD/PS19 mouse model.
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry, University Medicine Goettingen, Goettingen, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Saul
authors.forename: Frederik
authors.initials: F
authors.lastname: Sprenger
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; C054369:MAPT protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins
keywords: APP; Alzheimer; Aβ; Hyperphosphorylation; Neurodegeneration; Neuron loss; Synaptic pathology; Tau; Transgenic mice