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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.

Nedd5 is a septin protein enriched in brain and associates with the exocyst complex, a protein complex required for neurite outgrowth in neuroendocrine PC12 cells. In this study, we further investigate the association between Nedd5 and the exocyst complex as well as the role of Nedd5 in neurite outgrowth in differentiating PC12 cells. The endogenous Nedd5 is enriched at the perinuclear region in undifferentiated PC12 cells and radiates outward, from the perinuclear region toward the growth cone, upon NGF-induced PC12 neuronal differentiation. Nedd5, as well as other septin proteins, co-immunoprecipitates with the exocyst complex and tubulin from rat brain lysate. Interestingly, the over-expression of a GTPase-defective Nedd5 mutant promotes aberrant neurite sprouting in PC12 cells. These results demonstrate that Nedd5 and other septin proteins are associated with both the exocyst complex and microtubules and uncover a putative role for the Nedd5 GTPase activity in neurite outgrowth. Taken together, these findings suggest that Nedd5 may be required for polarized neurite outgrowth, perhaps, by facilitating the exocyst complex function during neuronal differentiation., (Copyright 2003 Lippincott Williams & Wilkins)