many neurodegenerative disorders are characterized by 
 their presence in neural tissue of aberrant protein aggregates 
 ( see table 1 ) . in general , these aggregates arise after the modification of a 
 native protein . that modification could result in a conformational 
 change of the native protein that promotes the aberrant 
 aggregation .
the most studied model of this mechanism has been the prion 
 protein where a change from an alpha helix to beta sheet structure 
 facilitates the polymerization of a protein with a different 
 conformation that appears to have a cytotoxic effect . in a similar way
, conformational changes between a native protein 
 and its aberrant protein counterpart with capacity for 
 self - assembly have been studied in many neurodegenerative 
 diseases . among the most common techniques used for these analyses 

are x - ray diffraction , nuclear magnetic resonance , circular 
 dichroism , or fourier - transformed infrared spectroscopy . 
 similarly , to the case of prion protein , in some disorders a 
 change from alpha helix to beta sheet conformation has been 
 suggested to cause protein aggregation ( table 1 ) , 
 probably because in alpha helix , intramolecular hydrogen bonds 
 could occur whereas intramolecular hydrogen bonds are facilitated 
 in beta sheet conformation , facilitating protein aggregation . 

however , there is one case , the formation of aberrant aggregates 
 of tau , where the aggregated protein contains also a high 
 proportion of alpha helix structure .
although , in some cases , like that of prion protein , the formation 
 of aberrant aggregates of protein could result in a toxic effect 
 in the affected neurons , in other cases , like huntingtin 
 aggregates , the formation of the aberrant aggregates could be a 
 survival response of the affected neurons .
in other 
 neurodegenerative diseases , it will be of interest to know if 
 protein aggregation is synonymous of cell toxicity or not .
protein conformation could also play a role in a possible toxic 
 mechanism . in this way
, a protein with a high proportion of alpha 
 helix and hydrophobic regions could be inserted in cell membrane 
 promoting toxic effects .
additionally , the presence of 
 aberrant polymers could affect the protein degradation cell machinery ( the proteasome complex ) , decreasing its activity 
 and promoting a toxic effect .
recently , some good reviews have been published on protein 
 aggregation and neurodegenerative disorders [ 6 , 7 ] . in this 
 review
we will mainly focus on those aggregates assembled from tau 
 protein , aggregates that could be present in the neurological 
 disorders known as tauopathies ( for a review see ) ( table 1 ) .
it has been described that large amounts of native or unmodified 
 tau protein were enough to promote tau assembly into fibrillar 
 polymers resembling those found in ad [ 912 ] .
thus , 
 obviously , an increase in tau concentration will favour the 
 formation of tau polymers .
recently , it has been reported that not 
 all the brain areas have a similar amount of tau protein 
 .
thus , it suggests a different probability in the formation of tau polymers in different brain regions .
the amount of tau will be the consequence of its synthesis and its 
 degradation .
changes in transcription have been indicated for 
 other proteins related to neurodegenerative disorders , where a tata binding protein may play a role .
tau degradation may 
 take place through the proteasome complex [ 15 , 16 ] and it has 
 been suggested that such degradation could be regulated by 
 posttranslational modifications occurring in tau molecule , like 
 its phosphorylation .
also , tau degradation by other proteases could be regulated by its level of phosphorylation 
 .
it should be also indicated that in some cases like parkinson 's disease or lafora disease , mutations in the e3 
 ubiquitin ligases like parkin   or malin   will 
 result in the appearance of aberrant protein aggregates . a conformational change , that could be followed by antibodies that 
 react with tau molecule after that conformational change 
 [ 2124 ] has been also suggested to be required for the 
 transition tau monomer - tau polymer . also , it has been suggested that different posttranslational 
 modifications like phosphorylation , glycation , 
 or truncation , may play a role in the formation of tau 
 polymers . due to the alternative splicing of its heterogenous ( or nuclear ) 
 rna , different tau isoforms could be expressed and , therefore , 
 different tau aggregates with different tau isoforms in different 
 tauopathies could occur , but we will not discuss this point here . 
 for further information see .
, it has been suggested that removal of the amino 
 and/or carboxy terminal regions , leaving the tubulin binding 
 region will facilitate tau polymerization [ 21 , 22 , 28 ] .
some work has been done in vitro   and in vivo [ 30 , 31 ] about a possible role of tau phosphorylation on tau 
 assembly , suggesting that in some conditions tau phosphorylation 
 may increase the capacity of tau for its self - assembly .
not only 
 an increase in serine / threonine phosphorylation of tau could 
 regulate its aggregation but also an increase in tau tyrosine 
 phosphorylation may increase the formation of tau aggregates 
 . this assembly process may involve the formation of oligomers   , filaments , and aggregates of filaments 
 ( tangle - like structures ) . in the formation of these aggregates of 
 filaments , glycation may play a role . the possible relation between phosphorylation and tau aggregation 

has been studied in transgenic mice expressing human tau bearing 
 some mutations found in human fronto - temporal dementia linked to 
 chromosome 17 ( ftdp-17 ) . in this mouse ,
tau 
 phosphorylation mainly occurs by gsk3 . when a specific 
 inhibitor of this kinase , lithium , was given to the transgenic 
 mice no tau phosphorylation was found , and in addition no 
 aggregation of the protein was detected   suggesting a 
 correlation between tau phosphorylation and aggregation in this 
 model .
this result was supported by an additional experiment using 
 another mouse also expressing human tau with a ftdp-17 mutation 
 .
alternatively , protein chaperones , acting on tau or in phosphotau , 
 could modify the level of tau aggregation , examples could be the 
 protein 14 - 3 - 3 , musashi-1   , or pin-1 
 [ 37 , 38 ] .
the chaperone associated ubiquitin ligase chip could 
 be able to target phosphotau for proteasomal degradation 
 [ 16 , 18 ] .
it has been described that tau binding to microtubules is regulated by the level of tau phosphorylation at some specific sites .
it is known that hyperphosphorylated tau binds with less affinity to microtubules resulting in the decrease in the interaction with microtubules , in a decrease of 
 microtubule stability , and probably in a microtubule dysfunction inside the cell that could result in a toxic effect 
 .
also , tau phosphorylation could result , as indicated above , in a decrease of its proteolysis .
more recently , it has been indicated that expression of a tau mutant ( p301l ) 
 could result in an increase of its phosphorylation , since once it is phosphorylated , that mutation can prevent the binding of those phosphatases involved in its dephosphorylation .
this 
 phosphotau could have a decreased capacity for microtubule binding 
 and it could be toxic for the cell . additionally , it has been 
 indicated that hyperphosphorylated tau can cause 
 neurodegeneration , in the absence of large tau aggregates 
 . on the other hand , only the overexpression of wild - type human tau in a mouse is sufficient to cause tau phosphorylation , aggregation , and neural toxicity . on the other hand
, it has been suggested that tau phosphorylation may represent a 
 protective function in ad .
sometime ago , the development of tau pathology , related with 
 dementia in ad , was clearly described by braak and braak 
  by following the development of neurofibrillary lesions at different stages of the disease . also , the formation of 
 neurofibrillary ( tau aggregates ) pathology within those neurons of 
 hippocampus and cerebral cortex affected at different stages was 
 found .
these neurons could degenerate yielding extracellular ghost 
 tangles ( enft ) . in the hippocampus
, an inverse relation has been found between the number of enft and the number 
 of surviving neurons [ 4851 ] .
it suggests that neurons that 
 degenerate , have previously developed tau aggregates . on the other 
 hand
, it has been indicated that neurons bearing neurofibrillary 
 lesions could survive for a long period of time , and , by comparing with other neurodegenerative disorders , like huntington 
 disease , it can be suggested that tau aggregates could protect against neurodegeneration by sequestering toxic ( phospho ? ) 
 monomeric tau that could be present in a high amount inside a cell 
 in pathological conditions . also , it has been suggested , using a 
 transgenic mouse model , that behavioural ( memory ) deficits could be unrelated to the formation of tau polymers , 

although , more recently , the discussion of those experiments suggested that hyperphosphorylated , aggregated tau intermediates could be the ones that cause neurodegeneration . in this way , the implication of different types of protein aggregates in neurodegeneration has been extensively 
 discussed [ 19 , 54 ] . a possibility about the existence of neurotoxic tau intermediate aggregates in human tauopathies
is 
 based in the fact that patients with ftdp-17 show an extensive 
 neurodegeneration with a high level of tau phosphorylation but 
 with a low number of tangles . in any case , even if the formation of tau aggregates has a 
 protective function for the neurons , that function is not working 
 well , as described by braak and braak , and afterwards by delacourte et al , indicating a correlation between 
 progression of tau pathology and progression of the disease .
this 
 idea is supported by those experiments indicating that neural loss 
 and neurofibrillary tangle number increase in parallel with the 
 progression of the disease .
similar results have been described in other neurological disorders like brain encelphalopathies , where the formation of aberrant polymers are related to the onset of neurodegeneration ; whereas this is far from clear in other disorders like 
 huntington disease .
examples of neurological diseases where aberrant protein 
 aggregates are found , and the suggested conformations in the 
 aberrant aggregates are indicated .
 protein aggregation takes place in many neurodegenerative 
 disorders . however , there is a controversy about the possible 
 toxicity of these protein aggregates . in this review , 
 this 
 controversy is discussed , focussing on the tau aggregation that 
 takes place in those disorders known as tauopathies . 
INTRODUCTION
TAU AGGREGATION
TOXICITY OF PHOSPHOTAU
TOXICITY OF AGGREGATED TAU
Figures and Tables