Extracellular Tau Oligomers Damage the Axon Initial Segment.

BACKGROUND: In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described. OBJECTIVE: Test the hypothesis that AIS structure is sensitive to xcTauOs. METHODS: Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors. RESULTS: Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles. CONCLUSION: xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.

Effects of Ivermectin Exposure on Regeneration of D. dorotocephala Planaria: Exploiting Human-Approved Ion Channel Drugs as Morphoceuticals.

Transformative applications in regenerative medicine await increased control of processes implementing repair and remodeling of complex living structures. Recent work reveals ion channel drugs as a powerful toolkit for modulating endogenous bioelectric circuits that control growth and form in vivo and in vitro. It is therefore especially important to develop assays in model systems that will enable the testing of these "morphoceuticals"-compounds with predictable effects on anatomical structure. The regenerative planaria are an ideal model system for this purpose. Several studies have shown a role for bioelectric signaling in planarian regeneration, but these have focused on Dugesia japonica and Schmidtea mediterranea. It is not known how the alterations of ion channel activity would affect regeneration in other species of planaria-an important aspect of building robust computational models of bioelectric circuits. Here, the effect of ivermectin (IVM), a chloride channel opener drug commonly used to combat heartworm is tested, on regeneration in a new species of planaria: Dugesia dorotocephala. Exposure to IVM during regeneration results in patterning abnormalities, such as bifurcated tails with partial heads, as well as delayed regeneration. These data extend our understanding of the effects of human-approved ion channel drugs on regenerative processes.