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Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.
This book presents essential studies and cutting-edge research results on tau, which is attracting increasing interest as a target for the treatment of Alzheimer's disease. Tau is well known as a microtubule-associated protein that is predominantly localized in the axons of neurons. In various forms of brain disease, neuronal loss occurs, with deposition of hyperphosphorylated tau in the remaining neurons. Important questions remain regarding the way in which tau forms hyperphosphorylated and fibrillar deposits in neurons, and whether tau aggregation represents the toxic pathway leading to neuronal death. With the help of new technologies, researchers are now solving these long-standing questions. In this book, readers will find the latest expert knowledge on all aspects of tau biology, including the structure and role of the tau molecule, tau localization and function, the pathology, drivers, and markers of tauopathies, tau aggregation, and treatments targeting tau. Tau Biology will be an invaluable source of information and fresh ideas for those involved in the development of more effective therapies and for all who seek a better understanding of the biology of the aging brain.
Cyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.
Filamentous tau pathologies are the hallmark lesions of several neurodegenerative tauopathies including Alzheimer's disease (AD) and corticobasal degeneration (CBD). These diseases show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. In the study, the rapid induction of tau pathology and the distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau in human mutant P301S tau transgenic (Tg) mice (line PS19) is analysed. At 1 mo post-injection of extracts obtained from brains with CBD pathology (CBD-Tau), tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of enriched tau extracts from brains with AD pathology (AD-Tau) in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 mo post-injection. With longer post-injection survival intervals of up to 6 mo, CBD-Tau and AD-Tau induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type specific pattern noted above. In conclusion, these experiments provide evidence for the prion-like hypothesis of disease spread and suggest that the tau pathology formed in vivo is dependent on the tau pathology in the preparation indicating that there are post-translational modifications or strains of tau protein that are responsible for the variation between diseases.
Alzheimer Disease (AD) is an age-dependent degenerative affliction that affects a large portion of the population. The AD brain harbors accumulations of both amyloid (A[function of]Ó) into plaques and accumulation of tau into neurofibrillary tangles (NFT) as well as severe neuronal cell loss. It has been challenging to develop a mouse model of AD that encompasses all of these pathological features but the triple transgenic mouse model of AD (3xTg-AD) does develop both A & beta; plaques and NFTs. In the present study, we aimed to determine if the 3xTg-AD mouse also develops neuronal loss similar to that seen in human brain. We also studied the effects of mouse genetic background strain on neuronal cell death in addition to A & beta; plaques and NFTs by crossing the 3xTg-AD model (mixed C57BL6/129SvJ strain) onto a strain more susceptible to cell death (FVB/N). After determining if mouse background strain affects AD-like neuropathology, further research could lead to clues as to what genetic differences between mouse strains lead to exacerbation of AD-like pathology. Though mice and humans undoubtedly differ from one another in many aspects, knowledge about the factors that affect the severity and/or progression of AD pathology in mice could lead us to new knowledge about factors that affect severity and progression of AD in humans. Our results indicate that whereas there is no significant neuron loss in the original 3xTg-AD mice, altering the background strain to FVB/N did increase the AD-like pathology. However, deficiency in complement protein C5 in the FVB/N strain abrogated all Aß plaques and tau pathology as well as neuronal cell loss. These results indicate that modulation of complement may offer a potentially effective treatment for AD victims and also underlines the dramatic impact that genetic variability can have on the progression of AD.
The progression of Alzheimer's disease is theorized to progress from amyloid pathology to tau pathology as shown in the amyloid cascade hypothesis. The pathway for this progression is, as of yet, unknown. Previous studies have shown a correlation between the presence of inducible nitric oxide synthase and the severity of Alzheimer's disease mouse models. Using mice carrying mutations in the amyloid precursor protein crossed with mice lacking inducible nitric oxide synthase we examined the link between disease progression and the presence of nitric oxide synthase. Additionally, mice carrying the amyloid precursor protein (APP) mutation in conjunction with a mutation in the caspase cleavage domain of APP were studied in the context of the ablation of inducible nitric oxide synthase. The mice were evaluated in terms of amyloid plaque load, levels of amyloid beta protein, and levels of hyperphosphorylated tau protein. There was no obvious correlation between the ablation of inducible nitric oxide synthase and the severity of Alzheimer's-like pathology. Mice carrying the caspase cleavage mutation showed a significant increase in amyloid plaque load when completely lacking inducible nitric oxide synthase compared to mice carrying the same mutations but with one copy of the inducible nitric oxide synthase gene.