Tauopathies are a family of
neurodegenerative diseases that have the pathological hallmark of intraneuronal accumulation of filaments composed of hyperphosphorylated
tau proteins that tend to aggregate in an ultrastructure known as neurofibrillary tangles. The identification of mutations on the tau gene in familial cases of
tauopathies underscores the pathological role of the
tau protein. However, the molecular process that underlines tau-mediated neurodegeneration is not understood. Here, a proteomics approach was used to identify
proteins that may be affected during the course of tau-mediated neurodegeneration in the
tauopathy mouse model JNPL3. The JNPL3 mice express human
tau proteins bearing a P301L mutation, which mimics the neurodegenerative process observed in humans with
tauopathy. The results showed that the
protein amphiphysin-1 (AMPH1) is significantly reduced in terminally ill JNPL3 mice. Specifically, the AMPH1
protein level is reduced in brain regions known to accumulate aggregates of hyperphosphorylated
tau proteins. The AMPH1
protein reduction was validated in
Alzheimer's disease cases. Taken together, the results suggest that the reduction of the AMPH1
protein level is a molecular event associated with the progression of tau-mediated neurodegeneration.