Garcia_edit_EU Neurology 08/03/2010 16:15 Page 20
Neurodegenerative Disease Alzheimer’s Disease
Pathology of the Cleaved Tau Protein in the Context of Toxicity and the
Formation of Neurofibrillary Tangles
Gustavo Basurto-Islas,
1
Siddhartha Mondragón-Rodríguez,
1
Lester I Binder
2
and Francisco García-Sierra
3
1. PhD Student, Department of Cell Biology, Centre of Research and Advanced Studies, National Polytechnical Institute, Mexico City; 2. Professor of Cell and
Molecular Biology, Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine; 3. Professor of Cell Biology and
Neuroscience, Department of Cell Biology, Centre of Research and Advanced Studies, National Polytechnical Institute, Mexico City
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-Rodríguez have received scholarship support from
CONACyT-Mexico and ICyT DF. Francisco García-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 García-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 understand the mechanisms involved in the genesis of the NFTs in AD.
characterised by memory loss and cognitive impairment in the elderly. Besides abnormal phosphorylation and conformational changes,
These symptoms are attributed to the accumulation of abnormal proteolysis of the tau protein is a newly emerging research area.
structures, namely amyloid-β (Aβ) plaques and neurofibrillary tangles Proteolysis contributes to the neuron toxicity and the formation of
(NFTs). The latter structures first appear in the entorhinal cortex and NFTs in AD.
13–17
This review discusses and summarises the relevance
parallel the clinical progression of the disease, as they spread out to of tau proteolysis as a new pathological modification that contributes
the limbic regions and then the isocortex.
1
to the formation of NFTs and the toxicity of these structures in AD.
This hierarchical distribution of NFTs correlates better with AD The Cleavage of Tau Protein and
progression than the deposition of Aβ.
2,3
Structurally, NFTs are made Its Relation to Alzheimer’s Disease
up of insoluble paired helical filaments (PHFs) composed of the To identify the minimum component that composes the PHFs, native
microtubule-associated protein tau, found mainly in a hyper- tau filaments isolated from the brains of AD patients were sonicated
phosphorylated state.
4,5
Polymeric tau has been considered toxic
6
in formic acid. They were then treated proteolytically, releasing a
because of this abnormally phosphorylated state, which potentially 12kDa fragment of the tau molecule as the major component. This
reduces its microtubule-binding capacity.
7,8
It is also toxic because of minimum component began in the vicinity of histidine-268 and
its abnormal redistribution to the somatodendritic compartment, contained the microtubule-binding domains. This fragment ended at
restricting the physical space and interfering with several processes, the C-terminus position, glutamic acid 391 (Glu
391
), and is referred to
such as the sorting of molecules and intracellular transport.
9–12
as the PHF-core.
15,18
Thereafter, the monoclonal antibody MN423 was
generated, which specifically recognises the Glu
391
-truncated tau in
These data have suggested a relevant role for NFTs as the major vitro and also the polymeric tau forming the neurofibrillary pathology
pathological structures that impose a pathological insult on central when it is assessed in the brain of AD patients (see Figure 1).
15,18,19
nervous system neurons in AD patients. For this reason it becomes Later, to determine the clinicopathological role of the Glu
391
-cleaved
crucial to analyse the pathological processing of tau protein to better tau in AD, the density of NFTs immunolabelled with MN423 was
20 © TOUCH BRIEFINGS 2009
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108  |  Page 109  |  Page 110  |  Page 111  |  Page 112  |  Page 113  |  Page 114  |  Page 115  |  Page 116  |  Page 117  |  Page 118  |  Page 119  |  Page 120  |  Page 121  |  Page 122  |  Page 123  |  Page 124  |  Page 125  |  Page 126  |  Page 127  |  Page 128  |  Page 129  |  Page 130  |  Page 131  |  Page 132