pFTAA: a high affinity oligothiophene probe that detects filamentous tau in vivo and in cultured neurons

PERSPECTIVE pFTAA: a high affinity oligothiophene probe that detects filamentous tau in vivo and in cultured neurons Tauopathies describe a group of neurodegenerative diseases in which the protein tau, encoded by the gene MAPT, is aberrantly misfolded, leading to tau aggregation, neural dysfunction, and cell death (Spillantini and Goedert, 2013). In Alzheimer's disease (AD), tau forms the characteristic intracellular neurofibrillary tangles (NFTs), which are thought to be the major cause of neu-rodegeneration (Bloom, 2014). In other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17T), corticobasal degeneration and progressive supranuclear palsy, there are specific forms of tau aggregates and filaments without any amyloid pathology, demonstrating tau's potent disease-causing potential (Spillantini and Goedert, 2013). Tau is a microtubule (MT) binding protein, which becomes abnormally hyperphosphorylated on several residues prior/during the process of aggregation, thereby causing loss of its MT binding activity (Mandelkow and Mandelkow, 2012). The importance of tau as a single cause of disease is reinforced by the identification of numerous (> 55) mutations in autosomal-dominant forms of familial tauopathies, many of which occur in the MT binding domain. Indeed, more and more diseases are being uncovered in which aberrant phosphorylation and folding of tau is implicated, not least in Huntington's disease (HD), while MAPT is a genetic risk factor for Parkinson's disease (PD), so it is of major interest to understand how it leads to cell dysfunction and death. Despite the propensity of tau to misfold, it has been difficult to demonstrate the presence of insoluble fibrils of tau in animal and living cell models. Indeed, even in the test tube, fibril formation of pure tau requires addition of polyanionic polymers, such as hepa-rin (Goedert et al., 1996). Many studies of tau have therefore relied on non-neuronal cell models where mutant tau is over-expressed to understand the causes of tau-related cell death. However, not only is the cellular milieu unlikely to be similar to that of neurons, but many cell lines express immortalising genes, making these cells prone to die by apoptosis whereas death by apoptosis in neurode-generation is rather rare. In most studies, even those involving primary central nervous system (CNS) neurons transfected with tau, cell death is only studied over a few days, unlike the case in human disease where neuronal death extends over decades. To address this problem, we sought a robust primary neuronal model of tauopathy, leading us to develop a culture system …