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

The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of beta-amyloid (A beta) 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 A beta 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 A beta toxicity by directly injecting A beta oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against A beta-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human A beta 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 A beta, which propagate toxicity after A beta has been cleared, may be tractable therapeutic targets.