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.

Current state of Alzheimer’s fluid biomarkers

“…Studies have shown elevated iron in AD [55, 226] and MCI [372] brains, which is also replicated in animal models [210]. Iron is a redox-active biometal that has been shown to bind Aβ in vitro and cause its aggregation, while releasing hydrogen peroxide [147].…”

Treating Alzheimer's disease by targeting iron

“…For example, tau knockout mice were shown to induce age‐dependent iron accumulation that resulted in neurodegeneration accompanying cognitive and motor impairment that can be rescued by iron chelation (Lei et al, ; Lei et al, ; Lei et al, ; Lei et al, ; Tuo et al, ). Intoxication of pathogenic species of Aβ in mice also resulted in tau‐dependent iron elevation (Li et al, ).…”

“…Intoxication of pathogenic species of Aβ in mice also resulted in taudependent iron elevation (Li et al, 2015).…”

Quantitative susceptibility mapping of brain iron deposition in patients with type 2 diabetes mellitus

“…Iron binds to amyloid-β to catalyze pro-oxidant radicals to be produced, thereby increasing the toxicity of peptide, which binds to tangles as well, leading to the formation of toxic radicals in neurons in a similar way (51). Synthetic amyloid-β intoxication in the mouse brain causes tau-dependent iron accumulation as well as cognitive impairment (52), which demonstrates that tau can mediate the effects of iron.…”