Garcia_edit_EU Neurology 08/03/2010 16:16 Page 22
Neurodegenerative Disease Alzheimer’s Disease
Figure 2: Conformational Changes and Abnormal Figure 3: Toxicity of Neurofibrillary Tangles Composed of
Phosphorylation in Tau Are Associated with the Truncated Tau in Alzheimer’s Disease Brains
Maturation of Neurofibrillary Tangles
High activity of astrocytes (glial fibrillary acidic protein positive) induced by the presence of
391
Conformational changes recognised by Tau-66 antibody (neurofibrillary tangles [NFTs] in green) neurofibrillary tangles composed of Glu -truncated tau (MN423-positive) causes a toxic
396
are associated with the phosphorylation of tau at pSer in matured NFTs (NFTs in blue). environment in the brain of Alzheimer’s disease patients.
is comparable to an aggregation process that develops slowly over of tau pathology and the disease. This idea is supported by
many years in the brain of those with AD is still an open question. observations indicating that neural loss and NFT density increase in
Therefore, more accurate information related to the toxicity and parallel with progression of the disease.
63,64
aggregation of truncated tau in the brains of authentic patients with
AD should be preferentially considered. It has been suggested that NFTs are more dynamic structures and
during their genesis the tau protein is progressively transformed from a
Tau Cleavage Associated with the Formation of linear non-folded protein to a conformationally altered entity that suffers
Neurofibrillary Tangles and Toxicity specific truncations along its extreme C-terminus.
8,24,34,65
The sequence in
The biological systems described above could only be considered which conformation changes and truncation occur in the pathological
models that attempt to reproduce the physiological conditions in processing of tau may predict the stage of evolution of the disease. The
which tau exerts its toxicity in the brains of patients with AD. For many, maturation of NFTs mainly depends on the state of proteolysis of the
aggregation of tau in distinct pathologies of the brain is a more C-terminus having, as an early event, the truncation at Asp
421
caused by
complex process. It involves interactions of multiple factors that may multiple caspases. The prevalence of this truncated protein in a
affect the functioning of interconnected neurons related to the polymeric state, which has been reported to be toxic in cell models, may
development of cognitive functions of the patients.
52
be one method of continuous damage in NFT-carrying neurons.
In situ, proteins are located and expressed in sufficient amounts to Proteolysis of tau is extended along the C-terminus during the
ensure the appropriate sorting and redistribution of intracellular evolution of AD, reaching a truncation event at the site Glu
391
at
components. One primary concern is the mechanism governing advanced stages of the disease, again contributing permanent toxicity
trafficking of tau from the axon to the somatodendritic compartment to the neurons
8
(see Figure 3). Validation of the clinicopathological
and whether the formation of a complex network of polymers can truly association between the progression of the disease and accumulation
interfere with normal cell function. Recent evidence pointed out this of NFTs composed by either Asp
421
or Glu
391
-truncated tau variants
effect of tau when polymers of this protein, introduced into the giant was recently described by the authors’ group.
13,65
Moreover, other
axon of the squid, caused interference with intracellular transport.
53
It is researchers have proposed that toxicity associated with NFTs may
known that tau polymers in the authentic disease are the result of also be based on the abnormal trapping properties of these
several post-translational modifications of the tau protein. These structures to sequester some cellular components that are important
modifications include phosphorylation,
54–56
conformational changes
24,57–59
for normal cell function. Thus, PHFs are able to sequester prolyl
and truncation.
13,16,17,34,60
Together, the modifications eventually lead to isomerase-1, a chaperone protein that binds to phosphoproteins
the formation of PHFs and, ultimately, NFTs (see Figure 2). containing phosphoserine or phosphothreonine followed by proline.
66
In the context of toxicity, NFTs are associated with neurons not Another protein with similar features is MAP1B, which in the aberrant
functioning well,
1,61,62
indicating a correlation between the progression phosphorylation state produced by a proline-dependent protein kinase
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