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14, Number 4, IN PRESS - Special Issue "Is Tau Aggregation Toxic or Protective?" (Guest Editors: Jesus Avila, George Perry, Mark A. Smith)
Jesus Avila, George Perry, Mark A. Smith
Preface: Is tau aggregation toxic or protective?
Khalid Iqbal, Alejandra del C. Alonso, Inge Grundke-Iqbal
Cytosolic Abnormally Hyperphosphorylated Tau But Not Paired Helical Filaments Sequester Normal MAPs and Inhibit Microtubule Assembly
Abstract: Neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of Alzheimer’s disease (AD) and related tauopathies, occurs both as cytosolic aggregated/oligomeric protein (AD P-tau) and as neurofibrillary tangles. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but, in the case of the cytosolic AD P-tau, also in a gain of a toxic function whereby the pathological tau sequesters not only normal tau, but also the other two neuronal microtubule associated proteins (MAPs), MAP1A / MAP1B and MAP2, and causes inhibition and disruption of microtubules. The sequestration of normal MAPs leads to a slow but progressive degeneration of the affected neurons. The affected neurons defend against the toxic tau by continually synthesizing new normal tau as well as by packaging the abnormally hyperphosphorylated tau into polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. The filamentous tau is inert; it neither interacts with tubulin and stimulates it assembly, nor binds to normal MAPs and causes disruption of microtubules. These findings suggest the inhibition of tau abnormal hyperphosphorylation and not the aggregation of tau as the preferred therapeutic target for AD and related tauopathies.
Akihiko Takashima
Hyperphosphorylated Tau is a Cause of Neuronal Dysfunction in Tauopathy
Abstract: Pathological studies show that neurofibrillary tangles are found in regions where neuronal death occurs. This observation raises the question: Are neurofibrillary tangles toxic or protective? Findings from various mouse models expressing human tau with the FTDP17 mutation suggest that some component involved in the formation of neurofibrillary tangles, rather than the neurofibrillary tangles themselves, might be responsible for the toxicity leading to neuronal death. Here, I review our current understanding of a toxic species of tau and the mechanism by which it contributes to neuronal dysfunction and death. Recent studies suggest that, before forming fibrils but after becoming hyperphosphorylated, tau is involved in neurodegenerative disease.
Rudy J. Castellani, Akihiko Nunomura, Hyoung-gon Lee, George Perry, Mark A. Smith
Phosphorylated Tau: Toxic, Protective, or None of the Above
Abstract: Identification of phosphorylated tau as the major protein component of neurofibrillary tangles (NFTs) led to the concept that phosphorylated tau was inherently toxic and, as such, intimately involved in Alzheimer’s disease (AD) pathogenesis. While superficially logical, this construct ignores a number of key findings in AD, including i) that NFTs are encountered in viable neurons until late stage disease; ii) that NFTs persist within the neuronal cytoplasm for decades; iii) that NFTs are encountered, sometimes in significant numbers, in cognitively intact elderly; and iv) that neurons with NFTs contain normal content and structure of microtubules. Experimental data in transgenic animal models has further demonstrated that NFTs accumulate in neurons in spite of tau suppression and behavior normalization. These data call into question the inherent toxicity of phosphorylated tau, seemingly leaving the only viable hypothesis of the ad hoc “toxic intermediate” phosphorylated tau concept. However, since we also know that phosphorylated tau sequesters redox active heavy metals and protects against oxidative stress, here we suggest that phosphorylated tau serves a protective role against cellular toxicity.
Jin-Jing Pei, Cecilia Björkdahl, Haiyan Zhang, Xinwen Zhou, Bengt Winblad
p70 S6 Kinase and Tau in Alzheimer’s Disease
Abstract: The 70-kDa S6 kinase (p70S6K) is a Ser/Thr (S/T)-directed kinase that plays a crucial role in cell growth, cell differentiation, and cell cycle control. This article presented evidence that supports both toxic and protective roles of p70S6K activity towards tau in Alzheimer’s disease (AD) brains. The p70S6K can phosphorylate tau at S262, S214, and T212 sites. Phosphorylation at these sites might release tau from microtubules, resulting in microtubule disruption. Evidence also suggests that p70S6K regulates the translation of tau mRNA by phosphorylating the 40S ribosomal protein S6. The extracellular amyloid-β deposition in AD brains could be a causative factor that activates p70S6K. We hypothesized that amyloid-β deposition activates p70S6K whose anti-apoptotic property subsequently keeps neurons from entering into the apoptotic process. This process provides the opportunity for the newly synthesized tau to be phosphorylated by p70S6K and by other tau kinases. This hyperphosphorylated tau then aggregates and is progressively deposited in neurons.
Kurt R. Brunden, John Q. Trojanowski, Virginia M-Y. Lee
Evidence That Non-Fibrillar Tau Causes Pathology Linked To Neurodegeneration and Behavioral Impairments
Abstract: The discovery that mutations within the tau gene lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) provided direct evidence that tau alterations can lead to neurodegenerative disease. While the presence of tau fibrils and tangles is a common feature of all tauopathies, including Alzheimer’s disease (AD), data are emerging from biochemical, cell-based and transgenic mouse studies which suggest that a pre-fibrillar form of pathological tau may play a key role in eliciting central nervous system neurodegeneration and behavioral impairments. Herein we review recent findings that implicate diffusible tau pathology in the onset of neurodegeneration, and discuss the implications of these findings as they relate to tau tangles and possible therapeutic strategies for the treatment of AD and related tauopathies.
Francisco García-Sierra, Siddhartha Mondragón-Rodríguez, Gustavo Basurto-Islas
Truncation of Tau Protein and its Pathological Significance in Alzheimer’s Disease
Abstract: Abnormal posttranslational modifications of tau protein lead it to aggregate into paired helical filaments in Alzheimer’s disease (AD). The mechanisms involved in the early pathological processing of tau and the induction of a polymeric state seem to progress through a sequential pattern of changes mainly involving abnormal phosphorylation, conformational changes and truncation. While proteolytic cleavage of tau protein during the progression of AD has not been comprehensively analyzed, tau is a substrate for several intracellular proteases. Furthermore, abnormal regulation of proteolytic events, including those associated with apoptosis, may generate truncated tau subproducts which in turn may be toxic to neurons per se and capable of polymerization at a faster rate. Accumulation of tau fibrils has long been controversial, with much debate concerning the true toxicity of polymerized tau. The development of different transgenic mice overexpressing tau protein, the generation of cell models expressing tau, and the in vitro polymerization paradigms have significantly enhanced our understanding of the biophysics and pathological properties of tau polymers in AD, as well as in other tau pathologies. This review will discuss the pathological role of truncated tau protein in the context of toxicity and neurofibrillary tangle formation and maturation and its significance in clinical dementia.
Carolyn A. Rankin, T. Chris Gamblin
Assessing the Toxicity of Tau Aggregation
Abstract: Abnormally phosphorylated and aggregated tau protein is the primary component of pathological structures that are closely associated with neurodegeneration in Alzheimer’s disease, Pick disease, corticobasal degeneration, progressive supranuclear palsy and many other neurodegenerative tauopathies, leading to the hypothesis that these structures are toxic mediators of disease progression. Results from animal models designed to test this hypothesis have yielded evidence that can suggest either a pathogenic, beneficial, or incidental role for tau aggregation. This review summarizes the differences in construction of recent model systems and assay methods that examine tau pathology and toxicity. We have found that the expression levels of tau and the modifications of tau used to enhance its aggregation have a large impact on the results. It is clear from the data that tau aggregation is toxic, but it is less clear which form of tau aggregate is the toxic species.
Nicolette S. Honson and Jeff Kuret
Tau aggregation and toxicity in tauopathic neurodegenerative diseases
Abstract: Since its discovery as a structural component of neurofibrillary lesions of Alzheimer’s disease more than twenty years ago, tau protein has been implicated in the cascade of events associated with neurodegeneration. Specifically, the "tau hypothesis" posits that misfunction of tau, which occurs in response to unknown stimuli, results in its intracellular assembly into filaments that eventually prove toxic to the cells that produce them. The tau hypothesis is supported by numerous neuropathological and genetic observations of authentic human disease cases. However, experiments designed to study aggregate toxicity in biological models suggest that some aggregate species may be inert or could potentially serve a neuroprotective function. Distinguishing these possibilities experimentally has been complicated by currently available biological models, which do not fully recapitulate aggregation conditions seen in disease. Additional model systems which better approximate physiological conditions may help elucidate the molecular mechanisms involved in aggregation associated toxicity. Here we examine the accumulated evidence linking aggregation and neurodegeneration, and experimental approaches to the problem of tau aggregation-mediated toxicity.
Jürgen Götz, Lars M. Ittner, Marcus Fändrich, Nicole Schonrock
Is Tau Aggregation Toxic or Protective: A Sensible Question in the Absence of Sensitive Methods?
Abstract: In Alzheimer’s disease brain, the microtubule-associated protein tau detaches from the microtubules, pathologically interacts with cellular proteins, and eventually forms insoluble aggregates that also bind and trap a myriad of proteins. As these proteins are depleted from the cellular pool, they are unavailable for physiological functions. Thus elevated tau levels are pathogenic, even in the absence of tau aggregation. Whereas it is reasonable to assume that tau aggregation is toxic during late stages of disease, the question arises whether early in disease it may be protective. This question can be addressed in tau transgenic animal models in which tau aggregation has been correlated with behavioral impairment. We discuss ways of how tau aggregation is monitored in these mice and what the detection limits are of these methods. We conclude that new tools are needed to measure the different stages of tau aggregation.
Alexis Bretteville, Emmanuel Planel
Is Tau Aggregation Toxic or Protective?
Abstract: Alzheimer's disease brains are characterized by extracellular aggregates of the amyloid-β peptide and intracellular neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein. The role of aggregated tau in neurodegeneration is still controversial, as evidence point to either a toxic or protective role in the disease. Here, we will first examine tau aggregation and its putative roles in Alzheimer’s disease. We will then review the findings concerning different species of tau and their potential toxicity.
André Delacourte
Tau Pathology and Neurodegeneration: An Obvious but Misunderstood Link
Abstract: Most dementing disorders result from a degenerating process named tauopathy. Alzheimer disease is the most frequent one, but only one among the large spectrum of tau-related diseases. Cognitive impairment is related, first of all, to the neocortical location of this degenerating process. However, the nature and the mechanisms leading to tauopathy can be very different. This is demonstrated by familial mutations on the tau gene as well as by the different morphological and biochemical patterns of tau lesions. Therefore there is no doubt that tau is an etiological agent. But the persistent and unsolved question is the basic mechanism leading to neurodegeneration: is it due to the toxic effect of aggregated tau, or a loss of tau function, or both? Some answers may come from a more focused interest towards sporadic tauopathies. Most of them are characterized by a degenerating process starting in a specific and vulnerable brain area and consuming the connected neuronal network, like a chain reaction. In other words, sporadic tauopathies are mostly a destabilization of specific neuronal networks that should be modeled for an efficient therapeutic approach.
Huiping Ding, Gail V. W. Johnson
The Last Tangle of Tau
Abstract: Tau aggregates into neurofibrillary tangles in Alzheimer’s disease and tauopathies. There is ongoing debate about whether tau aggregation is toxic and which form of tau is toxic. Based on recent studies showing that mature tau tangles can be dissociated from neuronal loss and cognitive deficits, it can be hypothesized that the intermediate pre-fibrillar tau aggregate is the predominant neurotoxic tau species. The toxicity of tau aggregation includes loss of physiological functions of native tau and gain of pathological functions of pre-fibrillar tau species. Mature tau tangles per se might be relatively inert or even represent failed cytoprotective efforts of protein quality control machineries in response to accumulating toxic tau species. Further studies on the mechanisms of tau aggregation, the structure of intermediate tau forms and their toxicity are needed to settle this debate.
Félix Hernández, Jesús Avila
Tau aggregates and tau pathology
Abstract: There is controversy in some neurodegeneration disorders whether the presence of aberrant aggregates in a neuron could have a toxic or a protective effect. In some disorders like in encephalopathies (prion disease), protein aggregates are toxic for the neuron. In other disorders, like Huntington disease, a protective role has been suggested for the aggregates of huntingtin. In this work, we comment about the role of tau aggregation. We suggest that tau aggregates could have an insufficient protective role in damaged neurons.
Erin E. Congdon, Karen E. Duff
Is Tau Aggregation Toxic or Protective?
Abstract: Abnormal protein deposits are a common feature of many human diseases including Alzheimer’s disease. In Alzheimer’s disease, the appearance of tangles, composed of the microtubule associated protein tau, correlates with both cell death and symptom severity. However, are tau filaments simply markers of disease progression, or are they directly responsible for cell death? Due to conflicting findings from cell and animal models, it remains controversial whether tau polymers or smaller pre-fibrillar aggregates or tau monomers are the toxic species. Indeed, if monomeric or oligomeric species are mediators of disease, formation of larger tau filaments may prove beneficial to affected cells. This review will examine the findings regarding the toxicity of various tau species.
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