From tau biology to tauopathy: Toward new therapeutic strategies

Abstract

Tau proteins belong to the family of microtubule-associated proteins. There are six Tau isoforms in the human brain. Tau isoforms regulate microtubule dynamics through their number of microtubule-binding domains (3 or4) and their state of phosphorylation: low levels of Tau phosphorylation allow for microtubule polymerization and stability; high levels of phosphorylation for microtubule depolymerization. Moreover, Tau proteins display an amino-terminal domain that is likely to bring them other specific biological functions including membrane interactions and DNA protection. Tau proteins aggregate in a number of neurodegenerative disorders referred to as Tauopathies, where they are always found hyperphosphorylated. However, inclusions found in Tauopathies are made of distinct sets of tau isoforms suggesting the existence of tau strains, similar to the prion strains. Another feature of Tauopathies reminiscent of prion-like disorders is that Tau aggregates can propagate amisfolded state to the inside of cells. Their microtubule-binding domains are likely to be crucial for the aggregation process since mutations in this area are found in fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, hyperphosphorylation may be an early toxic event before Tauproteins aggregate into filaments. To better understand the sequence of events leading to cell death and dementia, animal models have been developed. Nevertheless, most of these animal models are transgenic models over expressing tau with FTDP-17 mutations. One can ask if mutated tau really reflects this slow pathological process since mutations enhance aggregation rate of Tau proteins. Other models are thus needed. For proteomics analysis of Tau isoforms, human brains were obtained from the Lille NeuroBank and others. Animal models detailed in the present work are THY-Tau22 transgenic mice and a rat model obtained with stereotactic injections in the hippocampus of viral vectors encoding human tau (wild-type and mutated). In Alzheimer disease (AD), the Tau pathology is following cortico-cortical connections with a stereotyped, sequential and hierarchical pathway affecting large pyramidal neurons. Braak and Braak proposed a six stages spatiotemporal progression of Tau pathology in AD. Taupathology is also encountered in other neurodegenerative disorders. Our laboratory showed that depending on the neurological disorder considered, different sets of Tau protein isoforms were aggregated. For instance, the six Tau isoforms aggregate in AD whereas only three isoforms aggregate in Pick bodies of Pick's Disease. These observations suppose that subsets of Tau isoforms are expressed in sub neuronal populations, or alternatively, a defective splicing of Tau is an early event of neurodegeneration. Propagation of Tau pathology may also be specific to these different Tauisoforms. The use of animal models will be a key asset for understanding Taupathology. Using the Thy-Tau22 mouse transgenic line developed in our laboratory, analysis of the kinetics of Tauphosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a dys-connection between cognition deficits and neuronal cell death. This model exhibits progressive neuron-specific AD-like Tau pathology devoid of any motor deficits. A progressive development of Taupathology is observed in the hippocampus and amygdala, which parallels behavioural impairments as well as electrophysiological alterations. These latter changes are observed despite of any striking loss of neuronal/synaptic markers until 12 months of age in the hippocampus. In addition, in the hippocampus, hyper- and abnormally phosphorylated Tau species accumulate within the somato-dendriticarea, supporting a possible influence on hippocampal-dependent plasticity always confirmed by behavioural and electrophysiological evaluations. In conclusion, AD and other Tauopathies have likely different etioliges. They are characterized by differenct Tau aggregates, which may spread in different ways and explain their different clinical presentations. Animal models of Tau pathology may mimie part of the pathology (phosphorylation and/or aggregation, propagation vs. diffusion) and help for the development of new, innovative therapeutic strategies.