title: Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau.
abstract: The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased APP levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.
authors.affiliation: Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, 150001, China.|Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.
authors.forename: Xuling
authors.initials: X
authors.lastname: Li
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia. peng.lei@florey.edu.au.
authors.forename: Peng
authors.identifier: http://orcid.org/0000-0001-5652-1962
authors.initials: P
authors.lastname: Lei
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.|Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qingzhang
authors.initials: Q
authors.lastname: Tuo
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Ayton
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Moon
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.affiliation: Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, Victoria, Australia. ashley.bush@florey.edu.au.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000633:toxicity*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D007501:Iron; D010751:Phosphopyruvate Hydratase
keywords: Aging; Alzheimer’s disease; Iron; Neuroprotection; Tau; β-Amyloid