Tau Protein: Function and Pathology

Hanna Rosenmann, David Blum, Rakez Kayed, Lars M. Ittner
2012 International Journal of Alzheimer's Disease  
In the last decade, the fundamental role of the microtubuleassociated protein tau in neurodegeneration and dementia has been widely accepted. The generation of various transgenic models for tau pathology, varying in expressed mutations and driving promoters with either permanent (constitutive) or inducible expression, as well as the use of alternative animal models (fly, zebra fish, and rat) provided tools for studying mechanistic aspects of tau pathology and developing therapeutic approaches.
more » ... t is now well established that pathological forms of tau (hyperphosphorylated, aggregated, and truncated) are a major cause of dementia, rather than being only a secondary effect to the amyloid pathology in Alzheimer's disease (AD). There is a link between these two AD pathologies, tau and amyloid, with tau pathology being downstream to amyloid pathology, yet tau pathology can develop and respond independently of amyloid plaques. The direct evidence for tau pathology developing independently of amyloid, being sufficient to cause dementia and neurodegeneration, is the fact that there are various diseases with isolated tau pathology (frontotemporal dementia, Pick's disease, etc.), one disease with both pathologies (AD), while there is no dementia disease with isolated amyloid pathology without tau pathology present. These findings supported the concept that amyloid toxicity is tau dependent and that blocking/reducing the pathological effects of tau may be protective against the harmful effects of amyloid pathology, a concept that has indeed proven feasibility in various studies. Much evidence has been accumulated pointing to the contribution of tau to AD pathology by two mechanisms: loss of function (such as stabilization of microtubules) as well as gain of toxic function (aggregation and deposition as neurofibrillary tangles). Recently, new concepts emerge contributing to our understanding of the pathogenesis of tau pathology, particularly the identification of toxic soluble oligomers of tau, arguing for these isoforms being the main toxic forms of the taupathology; and the concept that tau pathology may spread in the brain by a prion-like mechanism, possibly involving a transsynaptic mechanism of spreading along anatomically connected networks. These accumulating data provide a better understanding of tau pathogenesis, and given the disappointing clinical outcomes of antiamyloid therapeutic approaches, led the scientific community to devote much more effort into studying tau pathology, and into developing tau-targeted therapeutic approaches, such as tau immunotherapy, kinase inhibitors, or microtubule stabilizers. In this Special issue of International Journal of Alzheimer's Disease, the investigators contributed review articles as well as original research articles that stimulate the continuing efforts towards understanding tau pathology in AD and other tauopathies as well as unravel the physiological functions of tau, in an effort to develop new treatments. The paper by the F. Van Leuven's group: "Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease," which discusses the relevance of tau in Alzheimer's disease and frontotemporal dementias. This concise and clear review covers the major discoveries and the many still remaining questions in the field.
doi:10.1155/2012/707482 pmid:22928147 pmcid:PMC3426215 fatcat:fdpzhc336ra45jqsuy6q2ky5wa