Truncation of Tau Protein and its Pathological Significance in Alzheimer's Disease

Garcı́a-Sierra, Francisco; Mondragón‐Rodríguez, Siddhartha; Basurto-Islas, Gustavo

doi:10.3233/jad-2008-14407

Cited by 83 publications

(61 citation statements)

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“…That is, phosphorylation itself requires other events, such as kinase deregulation, in which oxidative stress and metabolic homeostasis (discussed later) clearly play a role. In fact, some authors have suggested that the NFT deposits could just be a dynamic reservoir that reflects the kinetics of the disease [84]. …”

Section: Fibrillary Tau Deposition: Cause or Effect?mentioning

confidence: 99%

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Mondragón‐Rodríguez

Basurto-Islas

Lee

et al. 2010

Expert Review of Neurotherapeutics

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Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer's disease and have been the focus of disease etiology and pathogenesis. However, in the larger picture of a complex disease, the precise etiology of the lesions per se, as well as the clinical disease, remain to be defined. In this regard, to date no single process has been identified as a useful target and treatment efforts have shown no meaningful progress. Therefore, alternative ideas that may lead to new and effective treatment options are much needed. KeywordsAlzheimer's disease; amyloid; fibrillary deposits; oxidative stress; tau Amyloid plaques and neurofibrillary tangles (NFTs) are pathological hallmarks of the progression of Alzheimer's disease (AD). The questions of how, why and when they appear are, therefore, pertinent to understanding the disorder and, as a result, research efforts into the relationship between lesion and pathogenesis have been substantial. It is now known that specific molecular events are associated with the development of AD, although their exact relationship to lesion appearance is still controversial. Pathogenic mutations leading, for example, to amyloid-β (Aβ) deposition, are a primary piece of evidence [1][2][3], while a wide range of other metabolic abnormalities have been proposed [4][5][6][7][8]. During early AD stages, cell cycle deregulation has been related to the disease [9,10], which may also contribute to the protein aggregates. Other processes, such as oxidative damage to DNA and RNA, have † Author for correspondence: Tel.: +1 216 368 3670 Fax: +1 216 368 8964 mark.smith@case.edu.For reprint orders, please contact reprints@expert-reviews.com Financial & competing interests disclosureThis work was funded by NIH grant AG026151. Mark A Smith is, or has in the past been, a paid consultant for, owns equity or stock options in and/or receives grant funding from Anavex, Canopus BioPharma, Medivation, Neurotez, Neuropharm, Panacea Pharmaceuticals and Voyager Pharmaceuticals. George Perry is, or has in the past been, a paid consultant for and/or owns equity or stock options in Neurotez Pharmaceuticals, Panacea Pharmaceuticals, Takeda Pharmaceuticals and Voyager Pharmaceuticals. Xiongwei Zhu is a paid Advisory Board member for Medivation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Genetic events: causative, but how? NIH Public AccessPathogenic mutations leading to familial autosomal-dominant AD involve the Aβ precursor protein (APP) gene [22,23], and presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes [24]. Apolipoprotein E (APOE) polymorphisms, sometimes referred to as familial late-onset AD, are not mutations per se, but are a significant predisposing factor [25,26]. In particular, the APOE gene has three isoforms (ε2,...

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Section: Fibrillary Tau Deposition: Cause or Effect?mentioning

confidence: 99%

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Mondragón‐Rodríguez

Basurto-Islas

Lee

et al. 2010

Expert Review of Neurotherapeutics

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“…These NFTs are one of the primary pathophysiological hallmarks of Alzheimer disease (AD) and were originally suggested to play a major role in facilitating neuronal degeneration (1). However, recent studies now suggest that mature tangles may not be the toxic species (3,4). For example, in a repressible tau overexpression transgenic mouse model, turning off tau expression attenuated memory impairment and neuronal loss, whereas NFTs continued to accumulate (5).…”

mentioning

confidence: 99%

Caspase-cleaved Tau Expression Induces Mitochondrial Dysfunction in Immortalized Cortical Neurons

Quintanilla

Matthews-Roberson

Dolan

et al. 2009

Journal of Biological Chemistry

147

149

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In Alzheimer disease (AD) mitochondrial abnormalities occur early in the pathogenic process and likely play a significant role in disease progression. Tau is a microtubule-associated protein that is abnormally processed in AD, and a connection between tau pathology and mitochondrial impairment has been proposed. However, few studies have examined the relationship between pathological forms of tau and mitochondrial dysfunction. We recently demonstrated that inducible expression of tau truncated at Asp-421 to mimic caspase cleavage (T4C3) was toxic to immortalized cortical neurons compared with a fulllength tau isoform (T4). In this study we investigated the effects of T4C3 on mitochondrial function. Expression of T4C3 induced mitochondrial fragmentation and elevated oxidative stress levels in comparison with T4-expressing cells. Thapsigargin treatment of T4 or T4C3 cells, which causes an increase in intracellular calcium levels, resulted in a significant decrease in mitochondrial potential and loss of mitochondrial membrane integrity in T4C3 cells when compared with cells expressing T4. The mitochondrial fragmentation and mitochondrial membrane damage were ameliorated in T4C3 cells by pretreatment with cyclosporine A or FK506, implicating the calcium-dependent phosphatase calcineurin in these pathogenic events. Increased calcineurin activity has been reported in AD brain, and thus, inhibition of this phosphatase may provide a therapeutic target for the treatment of AD.Tau is a microtubule-associated protein which in a hyperphosphorylated state forms paired helical filaments; the major component of neurofibrillary tangles (NFTs) 3 (1, 2). These NFTs are one of the primary pathophysiological hallmarks of Alzheimer disease (AD) and were originally suggested to play a major role in facilitating neuronal degeneration (1). However, recent studies now suggest that mature tangles may not be the toxic species (3, 4). For example, in a repressible tau overexpression transgenic mouse model, turning off tau expression attenuated memory impairment and neuronal loss, whereas NFTs continued to accumulate (5). Furthermore, reduction of endogenous wild type tau attenuated behavioral abnormalities in an APP transgenic AD mouse model, in which substantial NFT pathology is absent (6). These and other findings suggest that a form or forms of tau that precede NFT formation may be the toxic species. There is increasing evidence that, in addition to aberrant phosphorylation, caspase cleavage of tau plays a role in the oligomerization and formation of a pathological tau species in AD (7,8). Tau is an in vitro substrate for caspase-3 and is readily cleaved at Asp-421, the caspase-3 cleavage site, located on the carboxyl-terminal end of the protein (7-10). This cleavage event results in a highly fibrillogenic tau isoform which in in vitro studies aggregates more readily and to a greater extent than full-length tau and facilitates aggregate formation of fulllength tau (7,8). Antibodies that specifically recognize Asp-421-truncated tau show ...

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“…Specific Tau-phosphorylation also alters microtubulebinding capacity and increase rate of filament nucleation (Chang et al, 2011;Fischer et al, 2009). With this issue, is proposed the sequential relationship between phosphorylation→ conformational change→ truncation, which can be repeated until Tau protein lost their Nand C-termini, exposing a minimal resistance protease region named PHF-core (figure 3) (Binder et al, 2005;García-Sierra et al, 2008;Wischik et al, 1985;Wischik et al, 1996). The dense core of PHFs is compound of the repeat region of the Tau protein, forming a fuzzy coat beside the filament with N-and C-termini of the protein (Skrabana et al, 2004).…”

Section: Tau Conformational Changes In Physiological and Pathologicalmentioning

confidence: 99%

Tau and Amyloid- Conformational Change to  -Sheet Structures as Effectors in the Development of Alzheimer's Disease

Anda-Hernández¹,

León²,

Mena³

et al. 2012

Neuroscience - Dealing With Frontiers

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Truncation of Tau Protein and its Pathological Significance in Alzheimer's Disease

Cited by 83 publications

References 100 publications

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Caspase-cleaved Tau Expression Induces Mitochondrial Dysfunction in Immortalized Cortical Neurons

Tau and Amyloid- Conformational Change to  -Sheet Structures as Effectors in the Development of Alzheimer's Disease

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