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  • Title: Long-term overexpression of heme oxygenase 1 promotes tau aggregation in mouse brain by inducing tau phosphorylation.
    Author: Hui Y, Wang D, Li W, Zhang L, Jin J, Ma N, Zhou L, Nakajima O, Zhao W, Gao X.
    Journal: J Alzheimers Dis; 2011; 26(2):299-313. PubMed ID: 21613741.
    Abstract:
    Intracellular tau aggregates composed of neurofibrillary tangles (NFTs) are a defining feature of Alzheimer's disease (AD). Increased expression of heme oxygenase-1 (HO-1) is a common phenomenon in AD. Interestingly, the spatial distribution of HO-1 expression is essentially identical to that of pathological accumulation of tau in AD. In this study, we developed a new transgenic mouse overexpressing HO-1, called CAG-HO-1 Tg mice, to explore the relationship between HO-1 and tau aggregation. In this model, we found that long-term overexpression of HO-1 significantly promoted tau aggregation in brain, by analyzing changes in morphology and insoluble tau expression levels. Moreover, our research provides the first in vivo evidence that HO-1 can enhance iron loading and tau (Ser199/202/396) phosphorylation in brains of transgenic mice. Cellular evidence indicates that HO-1 can induce the phosphorylation of tau through iron accumulation in Neuro2a cells stably transfected with HO-1. Our data suggest that long-term overexpression of HO-1 can promote tau aggregation. This mechanism involves excessive iron production mediated by HO-1 overexpression, which induces tau phosphorylation. Our results provide a potential pathway for the pathogenesis of tauopathies, which remains largely unknown.
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