Sensory Neurons from Tau Transgenic Mice and Their Utility in Drug Screening

Tau misfolding is a major cause of neurodegeneration, tauopathies being a growing group of diseases in which tau forms insoluble aggregates, best known in Alzheimer disease as neurofibrillary tangles (NFTs). Many transgenic mouse models of tauopathies have been generated, but it has been difficult to demonstrate disease in primary brain neurons from these mice because neurons need to be harvested within a few days of birth and tau fails to produce NFTs. Transgenic mice have been generated that express the 0N4R isoform of human tau mutated at amino acid 301 (P301S mice) under the Thy1.2 promoter. These mice, which model an inherited form of frontotemporal dementia, develop NFTs around 5 months of age. Taking advantage of the fact that Thy1.2 is expressed in the peripheral nervous system, we found that dorsal root ganglion (DRG) neurons express P301S tau and develop tau pathology along a similar time course to that found in central nervous system neurons in mice. Thus, NFTs are well-developed around 5 months of age. Because DRG neurons can be cultured from adult mice for months, they have proven to be an excellent model for studying how tau pathology develops and for screening compounds that may ameliorate tau pathology. Here we present a detailed protocol for the preparation of long-term DRG neuron cultures and describe how to study whether activation of autophagy ameliorates tau pathology.