Long-term overexpression of heme oxygenase 1 promotes tau aggregation in mouse brain by inducing tau phosphorylation

J Alzheimers Dis. 2011;26(2):299-313. doi: 10.3233/JAD-2011-102061.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Disease Models, Animal
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurofibrillary Tangles / genetics
  • Neurofibrillary Tangles / metabolism*
  • Neurofibrillary Tangles / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • tau Proteins
  • Heme Oxygenase-1