Background: The lack of diagnostic tools and disease-modifying treatments against Alzheimer’s
disease (AD) and related disorders, collectively known as tauopathies, has led to a socioeconomic
burden of epidemic proportion. Proteomics approaches can be used to identify novel proteome
changes that could help us understand the pathogenesis of tau-related pathological hallmarks and/or cellular
stress responses associated with tauopathy. These studies, however, need to be conducted taking
into consideration brain region specificity and stage of neurodegeneration in order to provide insights
about the pathological role of the identified proteins.
Methods: We used a tauopathy mouse model (JNPL3) that expresses human tau bearing a P301L mutation
and develops motor impairment, the severity of which correlates with the increased accumulation of
pathological tau. Tissue was dissected from asymptomatic and severely motor impaired JNPL3 mice as
well as non-transgenic littermate controls and subjected to two-dimensional gel electrophoresis. Differentially
abundant protein spots were identified by tandem mass spectrometry. Postmortem mild cognitive
impairment (MCI), AD and normal aging controls were used to validate the pathological significance
of the identified protein.
Results: Ezrin was identified as a protein that is upregulated in tau-mediated neurodegeneration. We
demonstrate that Ezrin protein abundance increased in JNPL3 mice preceded motor impairment and was
sustained in severely motor impaired mice. Ezrin expression was also increased in the temporal cortex of
MCI and AD patients.
Conclusion: The results demonstrate that increased Ezrin protein abundance changes are associated with
the early stages of neurodegeneration in tauopathy models and human disease. Understanding the role of
Ezrin in tauopathies such as AD may provide new insights for targeting tau-mediated neurodegeneration.