Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

• Published in: Neurotherapeutics 2015-10, Vol.12 (4), p.862-873
• Main Authors: Li, Xuling, Lei, Peng, Tuo, Qingzhang, Ayton, Scott, Li, Qiao-Xin, Moon, Steve, Volitakis, Irene, Liu, Rong, Masters, Colin L., Finkelstein, David I., Bush, Ashley I.
• Format: Article
• Language: English
• Subjects: Age Factors; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Enzyme-Linked Immunosorbent Assay; Exploratory Behavior - drug effects; Hippocampus - drug effects; Hippocampus - metabolism; In Vitro Techniques; Iron - metabolism; Maze Learning - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurobiology; Neurology; Neurosciences; Neurosurgery; Original; Original Article; Peptide Fragments - toxicity; Phosphopyruvate Hydratase - metabolism; Recognition, Psychology - drug effects; tau Proteins - genetics; tau Proteins - metabolism; Time Factors
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-015-0378-2

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.