Pathology of the Cleaved Tau Protein in the Context of Toxicity and the Formation of Neurofibrillary Tangles
Pathology of the Cleaved Tau Protein in the Context of Toxicity and the Formation of Neurofibrillary Tangles
European Neurological Review, 2009;4(2):20-3
Abstract
In Alzheimer’s disease, tau protein is abnormally processed to self-aggregate into pathologically paired helical filaments and neurofibrillary tangles. Accumulation of these structures in the somatodendritic compartment of neurons may result in pathological alterations of the cytoskeleton stability, abnormal sorting of molecules and obstruction of the intracellular transport of organelles. Initially, abnormal phosphorylation of tau was considered by many to be the major modification that alters its microtubule-binding capacity. In recent years, however, proteolytic cleavage of tau protein produced by caspases has been shown to promote the abnormal aggregation properties of tau in vitro and to produce toxic effects in cell and animal models of Alzheimer’s disease. Although some of these results have been debated, truncation of tau associated with neurofibrillary tangle formation has been shown to correlate well with the clinical progression of Alzheimer’s disease. Although new alternative mechanisms of tau pathogenesis in a monomeric or oligomeric state have been proposed, the aggregated form of intact or truncated tau into insoluble polymers is still a major indicator of neuronal degeneration.
Keywords
Alzheimer’s disease, neurofibrillary tangles, tau protein, caspases, truncation, confocal microscopy, conformational changes, apoptosis, tau polymerisation, neurodegeneration
Disclosure: The authors have no conflicts of interest to declare. Gustavo Basurto-Islas and Siddhartha Mondragón-RodrÃguez have received scholarship support from CONACyT-Mexico and ICyT DF. Francisco GarcÃa-Sierra has received financial support from CONACyT-Mexico (grant N° 59651).
Acknowledgements: Brain tissue was kindly donated by the Northwestern University Alzheimer’s Disease Center. The authors thank Drs Michael Novak, Lester Binder and Andre Delacourte for the use of the MN423, Tau-66 and AD2 antibodies, respectively. We also want to thank to Dr Ellis Glazier, who edited this English-language text.
Received: 18 February 2009 Accepted: 10 July 2009
Correspondence: Francisco GarcÃa-Sierra, Department of Cell Biology, Centre of Research and Advanced Studies of the National Polytechnical Institute, Av Instituto Politecnico Nacional 2508, CP 07360, Mexico City, Mexico. E: fgarcia-sierra@cell.cinvestav.mx
Alzheimer’s disease (AD) is the most common type of dementia and is characterised by memory loss and cognitive impairment in the elderly. These symptoms are attributed to the accumulation of abnormal structures, namely amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The latter structures first appear in the entorhinal cortex and parallel the clinical progression of the disease, as they spread out to the limbic regions and then the isocortex.1
This hierarchical distribution of NFTs correlates better with AD progression than the deposition of Aβ.2,3 Structurally, NFTs are made up of insoluble paired helical filaments (PHFs) composed of the microtubule-associated protein tau, found mainly in a hyperphosphorylated state.4,5 Polymeric tau has been considered toxic 6 because of this abnormally phosphorylated state, which potentially reduces its microtubule-binding capacity.7,8 It is also toxic because of its abnormal redistribution to the somatodendritic compartment, restricting the physical space and interfering with several processes, such as the sorting of molecules and intracellular transport.9–12
These data have suggested a relevant role for NFTs as the major pathological structures that impose a pathological insult on central nervous system neurons in AD patients. For this reason it becomes crucial to analyse the pathological processing of tau protein to better understand the mechanisms involved in the genesis of the NFTs in AD. Besides abnormal phosphorylation and conformational changes, proteolysis of the tau protein is a newly emerging research area. Proteolysis contributes to the neuron toxicity and the formation of NFTs in AD.13–17 This review discusses and summarises the relevance of tau proteolysis as a new pathological modification that contributes to the formation of NFTs and the toxicity of these structures in AD.
The Cleavage of Tau Protein and Its Relation to Alzheimer’s Disease
To identify the minimum component that composes the PHFs, native tau filaments isolated from the brains of AD patients were sonicated in formic acid. They were then treated proteolytically, releasing a 12kDa fragment of the tau molecule as the major component. This minimum component began in the vicinity of histidine-268 and contained the microtubule-binding domains. This fragment ended at the C-terminus position, glutamic acid 391 (Glu391), and is referred to as the PHF-core.15,18 Thereafter, the monoclonal antibody MN423 was generated, which specifically recognises the Glu391-truncated tau in vitro and also the polymeric tau forming the neurofibrillary pathology when it is assessed in the brain of AD patients (see Figure 1).15,18,19 Later, to determine the clinicopathological role of the Glu391-cleaved tau in AD, the density of NFTs immunolabelled with MN423 was correlated with the progression of neurofibrillary pathology determined by Braak staging criteria.1 More significantly, a positive correlation to the clinical severity of dementia was shown.13,14,20,21 Supporting the claim for the relevance of the cleavage of tau protein in AD, recombinant Glu391-cleaved tau showed increased rates of polymerisation in vitro over full-length tau.22 To explain this result, it was postulated that the C-terminus of tau could interfere with the polymerisation of this protein, caused by the folding of this region to the microtubule-binding repeats.22,23 Although Glu391 cleavage is an alternative mechanism involved in tau toxicity and aggregation, a candidate enzyme responsible for this cleavage under physiological conditions has not yet been identifed.24
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Alzheimer’s disease, neurofibrillary tangles, tau protein, caspases, truncation, confocal microscopy, conformational changes, apoptosis, tau polymerisation, neurodegeneration, treatment Alzheimer’s disease, Alzheimer’s disease symptoms,
