title: A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model.
abstract: Senile plaques formed by β-amyloid peptides (Aβ) and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau, a microtubule-associated protein, are the hallmark lesions of Alzheimer's disease (AD) in addition to loss of neurons. While several transgenic (Tg) mouse models have recapitulated aspects of AD-like Aβ and tau pathologies, a spatiotemporal mapping paradigm for progressive NFT accumulation is urgently needed to stage disease progression in AD mouse models. Braak and co-workers developed an effective and widely used NFT staging paradigm for human AD brains. The creation of a Braak-like spatiotemporal staging scheme for tau pathology in mouse models would facilitate mechanistic studies of AD-like tau pathology. Such a scheme would also enhance the reproducibility of preclinical AD therapeutic studies. Thus, we developed a novel murine model of Aβ and tau pathologies and devised a spatiotemporal scheme to stage the emergence and accumulation of NFTs with advancing age. Notably, the development of NFTs followed a spatiotemporal Braak-like pattern similar to that observed in authentic AD. More significantly, the presence of Aβ accelerated NFT formation and enhanced tau amyloidosis; however, tau pathology did not have the same effect on Aβ pathology. This novel NFT staging scheme provides new insights into the mechanisms of tau pathobiology, and we speculate that this scheme will prove useful for other basic and translational studies of AD mouse models.
authors.affiliation: Department of Pathology, Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hurtado
authors.forename: Laura
authors.initials: L
authors.lastname: Molina-Porcel
authors.forename: Michiyo
authors.initials: M
authors.lastname: Iba
authors.forename: Awo K
authors.initials: AK
authors.lastname: Aboagye
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins
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