although alzheimer 's disease ( ad ) and its main brain histopathology , that is , senile plaques and 
 neurofibrillary tangles ( nfts ) , were described a century ago , 
 significant research advances in the disease began only a few 
 decades ago . the discoveries of the major protein components of 
 senile plaques as amyloid -peptide [ 1 , 2 ] and of nfts 
 as abnormally hyperphosphorylated tau [ 3 , 4 ] in the 1980s 
 initiated a new era of ad research . since then , much research has 
 focused on the molecular mechanisms of initiation and formation of 
 the senile plaques and nfts and their roles in the pathogenesis of 
 ad . evidence accumulated in the last two decades indicates that 
 malprocessing of both tau and -amyloid precursor protein , 
 which produces -peptide , is pivotal , if not central , to the 
 molecular mechanism of ad . the severity of dementia symptoms in ad 
 strongly correlates to the number of nfts , but not of senile 
 plaques , in ad brains [ 59 ] , suggesting that tau 
 pathology might be associated with the disease mechanism more 
 directly . abnormal hyperphosphorylation of tau and its deposits in 
 the brain is also seen in several other neurodegenerative diseases 
 that are collectively named tauopathies ( for review , see 
 [ 10 , 11 ] ) . the discovery of tau mutations that cause 
 hereditary   frontotemporal dementia and parkinsonism linked to 
 chromosome 17   ( ftdp-17 ) [ 1214 ] further indicates that 
 tau abnormality alone is sufficient to produce dementia . therefore , for developing rational therapeutic 
 treatment of ad , it is essential to understand the molecular 
 mechanism by which tau abnormalities lead to neurofibrillary 
 degeneration . because tau aggregated in the brain of ad and all other 
 tauopathies is always abnormally hyperphosphorylated , numerous 
 studies have focused on the roles of the abnormal 
 hyperphosphorylation and the mechanism leading to tau 
 hyperphosphorylation . recent studies demonstrate that it is the 
 abnormal hyperphosphorylation that makes tau lose its normal 
 function to stimulate microtubule assembly , gain toxic activity , 
 and aggregate into nfts [ 1523 ] . in 
 addition to tau , several other brain proteins such as 
 neurofilaments , microtubule - associated protein ( map ) 1  b , 
 -tubulin , and -catenin are also found to be 
 hyperphosphorylated [ 2427 ] , suggesting that the 
 protein phosphorylation / dephosphorylation system might be 
 dysregulated in ad brain . because abnormally 
 hyperphosphorylated tau is pivotal to ad and has been extensively 
 studied , this review focuses on tau hyperphosphorylation . prevention and reversal of abnormal hyperphosphorylation of tau as 
 a potential promising therapeutic strategy is also discussed . tau was first discovered by weingarten et al   as a microtubule - associated protein that stimulates 
 microtubule assembly . there was not much research 
 interest in tau protein until a decade later , when it was found to 
 make up the paired helical filaments ( phfs ) that form nfts in ad 
 brain [ 3 , 4 , 29 ] . human tau gene was found on the long arm of 
 chromosome 17 ( position 17q21 ) and was found to contain 16 exons 
 . this single tau gene encodes six tau isoforms in adult 
 human brain as a result of alternative splicing of its mrna 
 . the six isoforms of tau differ from each other by the 
 presence or absence of one or two inserts ( 29 or 58 amino acids ) 
 in the n - terminal part and by the presence of either three or 
 four repeats in the c - terminal half . the repeats in the c - terminal half of tau are 
 the domains that bind to microtubules [ 3234 ] . the region 
 upstream of the microtubule - binding domains contains many proline 
 residues and , hence , is called the proline - rich region . the best - known biological functions of tau are to stimulate 
 microtubule assembly and to stabilize microtubule structure . tau 
 binds to microtubules via its microtubule - binding domains located 
 at the c - terminal half of the molecule [ 3234 ] . the 
 n - terminal part projects from the microtubule surface , where it 
 may interact with other cytoskeletal elements and the plasma 
 membrane [ 35 , 36 ] . each of the six tau isoforms possibly has 
 its particular physiological roles and differential biological 
 activities , because they are differentially expressed during 
 development and have different activities to stimulate microtubule 
 assembly [ 37 , 38 ] . only the shortest isoform of tau is 
 expressed in fetal brain , whereas all six isoforms are seen in 
 adult brain [ 39 , 40 ] . in addition to stimulating microtubule 
 assembly , several studies have suggested that tau may have other 
 physiological functions . it appears to interfere with binding of 
 kinesin and kinesin - like motors to microtubules , leading to a 
 preferential inhibition of plus - end - directed axonal transport 
 . overexpression of tau inhibits kinesin - dependent 
 trafficking of vesicles , mitochondria , and endoplasmic reticulum 
 . this may explain the symptoms of amyotrophic lateral 
 sclerosis with neurofilament accumulation in motor neurons of 
 several transgenic models of tau overexpression 
 [ 4346 ] . tau has been found to interact with 
 mitochondria , plasma membrane , and nucleic 
 acids [ 48 , 49 ] , suggesting that it may act as a mediator 
 between microtubules and these organelles . tau also appears to 
 interact with src - family nonreceptor tyrosine kinases such as fyn 
 [ 50 , 51 ] and phospholipase c- [ 52 , 53 ] via 
 its proline - rich region . these data suggest that tau may also play 
 a role in the signal transduction pathways involving src - family 
 tyrosine kinases and phospholipase c-. however , the physiological significance of these interactions remains to be 
 elucidated . as early as 1977 , tau was found to be a phosphoprotein . 
 in 1984 , it was demonstrated that phosphorylation of tau 
 negatively regulates its activity in promoting microtubule 
 assembly . because tau is abnormally hyperphosphorylated 
 in ad and other tauopathies , tau phosphorylation has been studied 
 extensively . normal brain tau contains 2 or 3 moles of phosphates 
 per mole of tau [ 5658 ] . studies on human brain biopsy 
 tissue indicated that several serine and threonine residues of tau 
 are normally phosphorylated at substoichiometrical levels 
 [ 59 , 60 ] . a normal level of phosphorylation appears to be 
 required for tau 's optimal function , whereas the 
 hyperphosphorylated tau loses its biological activity [ 15 , 
 16 , 6169 ] . the discovery that tau aggregated in ad brain is abnormally 
 hyperphosphorylated has stimulated many studies on the extent and 
 sites of tau hyperphosphorylation and their role in the 
 pathogenesis of ad . the phosphorylation level of tau isolated from 
 autopsied ad brains is 3- to 4-fold higher than that from normal 
 human brains [ 5658 ] . in addition , the hyperphosphorylated 
 tau is accumulated in both brains [ 70 , 71 ] and cerebral 
 spinal fluid [ 7280 ] of individuals with 
 ad . all six isoforms of tau are aggregated into phfs in the 
 abnormally hyperphosphorylated forms in ad brains [ 3 , 4 , 31 , 81 ] . to date , at least 37 serine and threonine residues have been 
 found to be phosphorylated in phf - tau ( for review , see ) . these residues include thr39 , ser46 , thr69 , thr123 , ser137 , 
 thr153 , thr175 , thr181 , ser198 , ser199 , ser202 , thr205 , ser208 , 
 ser210 , thr212 , ser214 , thr217 , thr231 , ser235 , ser237 , ser238 , 
 ser241 , ser262 , ser285 , ser305 , ser324 , ser352 , ser356 , ser396 , 
 ser400 , thr403 , ser404 , ser409 , ser412 , ser413 , ser416 , and 
 ser422 . many of these residues are also phosphorylated in normal 
 human brains without nfts at smaller extents , but they are rapidly 
 dephosphorylated during postmortem delay and tissue processing 
 [ 59 , 60 ] . however , the phosphate groups at these sites are 
 not readily dephosphorylated during the postmortem period and 
 tissue processing of ad brain , probably because of the deficient 
 protein phosphatase activities [ 8389 ] . some of the phosphorylation sites seen in phf - tau are not phosphorylated at all in normal brains . because all of the previously identified phosphorylation sites of 
 normal tau and phf - tau are at either serine or threonine residues , 
 it was thought that tau was phosphorylated only at serine and 
 threonine residues . however , recent studies suggest that tau in 
 developing brain and in ad brain is also phosphorylated at 
 tyrosine residues . the src - family nonreceptor tyrosine kinase fyn 
 can bind to and phosphorylate tau in vitro and in transfected 
 cells [ 50 , 51 , 93 ] . tyrosine phosphorylated tau at this position is 
 also seen immunohistochemically in the brain of transgenic mice 
 that express mutated human taup301l . williamson et al   demonstrated that in primary human and rat brain cortical cultures tau is phosphorylated at tyr 29 upon 
 treatment with a. the tyrosine phosphorylation of tau 
 appears rapid and transient . interestingly , antibodies specific to 
 tyrosine phosphorylated tau labeled purified phf - tau , but not 
 normal tau , suggesting that phf - tau is phosphorylated at the 
 tyrosine residues [ 93 , 94 ] . in addition , tyr394 was also 
 found to be phosphorylated in phf - tau and in tau from fetal 
 brains , and the phosphorylation at this site is catalyzed by 
 another nonreceptor tyrosine kinase c - abl . it is not 
 clear if the phosphorylation at any of the above tyrosine residues 
 is stoichiometrically significant . therefore , whether the tyrosine 
 phosphorylation of tau has any pathophysiological relevance 
 remains to be elucidated . numerous studies have demonstrated the important role of abnormal 
 hyperphosphorylation of tau in its aggregation into nfts and in 
 alzheimer 's neurofibrillary degeneration . in cultured cells , hyperphosphorylation of tau after treatment with phosphatase 
 inhibitors impairs its activity to bind to microtubules and 
 induces filamentous aggregation of tau . pseudohyperphosphorylated tau that simulates abnormally 
 hyperphosphorylated tau by mutation of serine or threonine 
 residues into glutamate at selected ad - related sites exerts a 
 cytotoxic effect , whereas wild - type tau is neutral . in 
 contrast , neurons from tau - knockout mice are resistant to a-induced neurotoxicity . overexpression of human tau in 
 combination with phosphorylation by drosophila gsk-3 homologue shaggy , but not tau overexpression alone , exacerbates 
 tau - induced neurodegeneration and results in the formation of 
 nft - like filamentous tau aggregates . this study shows a 
 causal relationship between tau hyperphosphorylation and 
 neurofibrillary degeneration in vivo . a study in disabled-1 ( an 
 adapter protein ) knockout mice further demonstrates that tau 
 hyperphosphorylation causes early death of the animals . most importantly , tau in inclusions of all tauopathies in human 
 and animal models is always hyperphosphorylated ( for reviews , see 
 [ 11 , 98 ] ) . abnormal hyperphosphorylation of tau appears to 
 precede its aggregation into nfts in ad brain [ 57 , 99101 ] . taken together , these studies suggest that the 
 abnormal hyperphosphorylation of tau is crucial to neurofibrillary 
 degeneration in ad and other tauopathies . 
  the largest isoform of human brain tau ( 441 amino acids ) contains 
 80 serine and threonine residues and five tyrosine residues 
 . phosphorylation at nearly half of these residues has 
 been reported in phf - tau ( see   for review ) . many studies 
 have demonstrated that phosphorylation of tau at different sites 
 has different impacts on its biological function and on its 
 pathogenic role . for instance , a quantitative in vitro study 
 demonstrated that phosphorylation of tau at ser262 , thr231 , and 
 ser235 inhibits its binding to microtubules by 35% , 
 25% , and 10% , respectively . in cultured 
 cells , phosphorylation of tau at ser214 and ser262 decreases its 
 binding to microtubules and appears to inhibit its assembly to 
 filaments . in vitro kinetic studies of the binding 
 between hyperphosphorylated tau and normal tau suggest that 
 phosphorylation of tau at ser199/ser202/thr205 , thr212 , 
 thr231/ser235 , ser262/ser356 , and ser422 are among the critical 
 phosphorylation sites that convert tau to a toxic molecule to 
 sequester normal maps from microtubules . further 
 phosphorylation at thr231 , ser396 , and ser422 promotes 
 self - assembly of tau into filaments . similarly , tau mutated at 
 ser396 and ser404 ( changing ser into glu ) to mimic phosphoserine 
 is more fibrillogenic than wild - type tau , and a tau 
 construct in which ser422 is mutated to glu shows a significantly 
 increased propensity to aggregate . consistent with 
 these observations is that mutation of ser422 to ala prevents 
 a-induced tau aggregation . these results 
 suggest that phosphorylation of ser422 may play a key role in tau 
 filament formation in vivo . an important question is , by what mechanism is the tau abnormality 
 involved in the pathological cascades that lead to 
 neurodegeneration in ad and other tauopathies . does a 
 hyperphosphorylation - induced defect in its activity to stimulate 
 microtubule - assembly contribute to cell dysfunction ? although 
 tau loses its activity to stimulate microtubules , lack of overt 
 phenotype of tau knockout transgenic mice   suggests that 
 it is very unlikely that tau abnormality contributes to 
 neurodegeneration via loss of normal function due to its 
 hyperphosphorylation . by a series of studies , we have found that 
 both the abnormally hyperphosphorylated tau isolated from ad brain 
 and in vitro hyperphosphorylation tau gain a toxic activity to 
 sequester normal tau and other maps , such as map1 and map2 , and 
 cause microtubule disassembly [ 16 , 18 , 66 , 108 ] . upon 
 dephosphorylation polymerization 
 of the hyperphosphorylated tau into phfs also abolishes this toxic 
 activity ( alonso a et al , unpublished observation ) . hence , we 
 speculate that the abnormal hyperphosphorylation of tau causes 
 neurodegeneration by gain of toxic activity rather than by loss of 
 normal activity that can be compensated for by other maps and that 
 formation of phfs / nfts from the hyperphosphorylated tau in neurons 
 is a defense mechanism by which neurons aim to reduce the toxic 
 activity of the abnormally hyperphosphorylated tau . conditional 
 overexpression of gsk-3 in the transgenic mouse brains 
 induces tau hyperphosphorylation and neurodegeneration , but no tau 
 aggregation . in contrast , there are nfts but no memory 
 loss in several lines of tau transgenic mice ( for review , see 
 ) . this phenomenon is probably common to other diseases 
 characterized by abnormal protein aggregates such as huntington 
 disease and cardiomyopathy , in which the abnormal , nonfibrillar 
 protein oligomers , rather than the aggregates themselves , appear 
 to be pathogenic [ 111 , 112 ] . to understand the mechanism leading to abnormal 
 hyperphosphorylation of tau in ad , protein kinases and 
 phosphatases that regulate tau phosphorylation level must be 
 identified first . in the last two decades , numerous studies aimed 
 to the identification of tau kinases and phosphatases have been 
 carried out . it was found that in vitro , dozens of 
 phosphoseryl / phosphothroenyl protein kinases and most of the major 
 protein phosphatases could act on tau protein at various 
 phosphorylation sites ( for reviews in detail , see [ 82 , 113 , 114 ] ) . tau appears to be a universal substrate for protein kinases 
 and phosphatases in vitro . this may not be surprising , because 
 nearly 20% of the amino acid residues of tau molecule are serines 
 and threonines , and nearly 50% of these residues are 
 phosphorylated to certain degrees in ad brain ( see   for 
 review ) . however , it is unlikely that all these enzymes that act 
 on tau in vitro catalyze tau phosphorylation / dephosphorylation in 
 vivo . immunohistochemical studies also have shown a colocalization 
 of more than a dozen protein kinases and several protein 
 phosphatases with nfts of ad brain . as we now know that nfts are 
 very  sticky  structures that can be stained 
 immunohistochemically by antibodies to numerous antigens , 
 immunohistochemical colocalization with nfts can only support 
 other data that indicate a role of the specific protein or enzyme 
 in the formation of nfts , but itself can not indicate such a role . further studies in cultured cells , in situ , and especially in vivo 
 suggest that a few protein kinases and phosphatases may be 
 involved in regulation of tau phosphorylation in the brain . the 
 kinases that most likely play a role in phosphorylation of tau in 
 the brain include glycogen synthase kanase-3 ( gsk-3 ) , cyclin - dependent kinase 5 ( cdk5 ) , camp - dependent 
 protein kinase ( pka ) , stress - activated protein kinases , and 
 calcium / calmodulin - dependent kinase ii ( camk - ii ) . the 
 sites of tau phosphorylation by these kinases , except 
 stress - activity protein kinases , have been summarized in our 
 recent review . among protein phosphatases , pp2a has been 
 shown to be the major tau phosphatase in the brain [ 69 , 
 116120 ] . in a recent study , we compared the catalytic 
 kinetics of tau dephosphorylation by various major brain protein 
 phosphatases and determined the relative contributions of these 
 phosphatases to the regulation of tau phosphorylation 
 quantitatively . we found that pp2a accounts for 70% of 
 the total tau phosphatase activity , whereas pp1 , pp2b , and pp5 
 each accounts for only 10% of the total tau phosphatase 
 activity . because pp2b activity is upregulated rather 
 than downregulated in ad brain , it is unlikely that it regulates 
 tau phosphorylation in vivo . accumulated evidence indicates that tau phosphorylation is 
 regulated by several protein kinases and that more than one kinase 
 might be involved in abnormal hyperphosphorylation of tau in ad 
 brain . interestingly , gsk-3 phosphorylates tau at both 
 prime sites ( ie , tau needs to be primed by phosphorylation with 
 other kinases at other sites ) and unprimed sites 
 [ 122126 ] . in a cotransfection study , 
 cho and johnson   found that a gsk-3 
 mutant ( gsk-3-r96a ) that only phosphorylates unprimed sites has no 
 negative impact on tau 's ability to bind to microtubules , in 
 contrast to wild - type gsk-3 , which significantly impairs 
 tau 's ability to bind to microtubules . further studies demonstrate 
 that primed phosphorylation of tau at thr231 by gsk-3 plays a critical role in decreasing tau 's ability to both bind to 
 and stabilize microtubules . in rat brains , activation of pka not only induces primed phosphorylation of tau by 
 gsk-3 , but also impairs the spatial memory of rats 
 [ 124 , 127 ] . gsk-3 appears to be regulated by both 
 phosphoinositol-3 kinase and protein kinase c 
  pathways 
 [ 128131 ] . an obvious approach to understanding how tau becomes abnormally 
 hyperphosphorylated in ad is to study whether tau kinase(s ) or tau 
 phosphatase(s ) are dysregulated in ad brain . several studies have 
 focused on whether the activities and expression of these enzymes 
 are altered in ad brain . among protein kinases , cdk5 was reported 
 to be upregulated in ad brain by one laboratory , but 
 this result was challenged by others [ 133136 ] . on 
 the other hand , both the activity and the expression of pp2a as 
 well as the activities of pp1 and pp5 are decreased in the 
 selected areas of ad brain [ 8389 ] . consistent with this finding , several other neuronal proteins such as neurofilaments , map1b , -tubulin , and -catenin are 
 also hyperphosphorylated in ad brain [ 2427 ] . hence , it 
 appears that downregulation of the phosphatases , especially of 
 pp2a , might underlie the abnormal hyperphosphorylation of tau and 
 other proteins in ad brain . studies of metabolically active rat 
 brain slices and transgenic mice suggest that the downregulation 
 of pp2a may produce hyperphosphorylation of tau , not only by the 
 deficient dephosphorylation of tau , but also through the 
 activation of several pp2a - regulated protein kinases , including 
 pka , camk - ii , map kinases , and 
 stress - activated protein kinases [ 139141 ] . nevertheless , 
 inhibition of pp2a activity in animal brain could only induce 
 hyperphosphorylation of tau at some of the hyperphosphorylation 
 sites seen in phf - tau , but does not result in nfts . attempts to 
 produce massive tangles of phfs in animal models merely via 
 alteration of tau phosphatase and/or kinase activities have not 
 yet been successful . these observations suggest that the 
 downregulation of tau phosphatases in ad brain may be only 
 partially responsible for the abnormal hyperphosphorylation of 
 tau . the causes leading to decreased pp2a activity in ad brain are not 
 well understood . downregulation of pp2a expression   and 
 upregulation of pp2a endogenous inhibitor proteins 
 i1pp2a and i2pp2a   in ad 
 brain may both contribute to the downregulation of pp2a activity . because the activities of pp1 [ 83 , 88 ] and pp5 [ 88 , 89 ] , 
 which contribute to regulation of tau phosphorylation to a much 
 smaller extent than pp2a , are also decreased in ad 
 brain , there might be a common factor that downregulates the 
 activities of the major brain protein phosphatases in ad brain . in addition to tau kinases and phosphatases , alterations of tau 
 itself , the substrate of these enzymes , may also play an important 
 role in its abnormal hyperphosphorylation and conversion into 
 phfs . tau is also modified post - translationally by 
 -n - acetylglucosamine ( glcnac ) via a glycosidic bond at 
 the hydroxyl groups of serine and/or threonine residues , and this 
 modification is called o - glcnacylation [ 143145 ] . 
 because o - glcnac could modify the same serine or threonine 
 residues of tau as phosphate does and a reciprocal relationship 
 between o - glcnacylation and phosphorylation has been seen in 
 many proteins ( for review , see ) , o - glcnacylation 
 could affect phosphorylation of tau . recent studies in various 
 systems found that tau phosphorylation is indeed regulated by 
 o - glcnacylation inversely [ 144 , 145 , 147 ] . most 
 interestingly , fasting of mice induces downregulation of tau 
 o - glcnacylation , which relies on glucose metabolism to supply 
 udp - glcnac as a donor for protein o - glcnacylation , and in turn 
 leads to hyperphosphorylation of tau . these findings 
 led to the novel hypothesis that impaired glucose 
 uptake / metabolism in ad brain , which was well established decades 
 ago , contributes to the disease pathogenesis via downregulation of 
 tau o - glcnacylation and , consequently , upregulation of tau 
 phosphorylation that leads to neurofibrillary degeneration 
 . classical n - linked glycosylation is a modification of protein at 
 asparagine residues by oligosaccharides , which normally modifies 
 only membrane proteins and secreted proteins . tau in ad brain , but 
 not in normal human brain , was found to be modified by 
 n - glycosylation [ 68 , 149 , 150 ] , and this aberrant tau modification appears to precede and facilitate abnormal 
 hyperphosphorylation of tau [ 150152 ] . there is no doubt that the abnormality of tau plays a central role 
 in neurofibrillary degeneration in ad and other tauopathies . a 
 critical review of the literature accumulated in the last two 
 decades sheds light onto the probable mechanism of neurofibrillary 
 degeneration of ad ( figure 1 ) . tau is the major microtubule - associated protein of mature neurons 
 where it stimulates microtubule assembly and stabilizes 
 microtubule structure . the phosphorylation level 
 of tau is regulated by tau kinases and tau phosphatases , as well 
 as by the alteration of tau itself . in ad and probably also in 
 other tauopathies , metabolic and genetic abnormalities lead to 
 dysregulation of signal transduction pathways , which in turn 
 causes an imbalance of the phosphorylation / dephosphorylation 
 system , that is , downregulation of pp2a in the brain . this 
 imbalance results in increased phosphorylation ( ie , 
 hyperphosphorylation ) of tau . the impaired brain glucose 
 uptake / metabolism that precedes ad also facilitates 
 hyperphosphorylation of tau via downregulation of tau 
 o - glcnacylation . aberrant n - glycosylation of tau in 
 ad brain also makes tau a more favorable substrate for major tau 
 kinases and less favorable for tau phosphatases [ 151 , 152 ] , 
 thereby facilitating tau hyperphosphorylation . the abnormally hyperphosphorylated tau resulting from any of the 
 above causes not only loses its biological activity to stimulate 
 microtubule assembly , but also becomes a toxic molecule , 
 sequesters normal tau , map1 , and map2 , and causes disassembly of 
 microtubules . the breakdown of the microtubule network in the 
 affected neurons compromises axonal transport and leads to 
 retrograde degeneration , which in turn results in neuronal death 
 and dementia . on the other hand , the abnormally 
 hyperphosphorylated tau detached from microtubules is not only 
 easier to polymerize into phfs as a result of 
 hyperphosphorylation , but it also causes increased intraneuronal 
 soluble tau concentration due to sequestration of normal tau from 
 microtubules , which further facilitates tau aggregation into phfs . the polymerized abnormal tau is further modified by 
 ubiquitination , glycation , polyamination , nitration , and 
 truncation ( for review , see ) , and forms mature 
 phfs / nfts . unlike the unpolymerized hyperphosphorylated tau that 
 is toxic , phfs / nfts appears to be inert ( alonso a et al unpublished observation ) , but these lesions grow in size 
 with disease progression and eventually might physically choke the 
 affected neuron to death . because neurofibrillary degeneration plays a central role in the 
 pathogenesis of ad , one of the most attractive therapeutic targets 
 of ad is to inhibit neurofibrillary degeneration . as outlined in 
 figure 1 , the most promising approaches to achieve 
 this goal are to inhibit the abnormal hyperphosphorylation of tau 
 and to inhibit its sequestration of normal maps . the former 
 approach is more effective since it should both rescue the 
 disruption of microtubule and axoplasmic flow and prevent further 
 deposition of nfts . several academic groups and pharmaceutical 
 companies have been investigating this approach by restoring pp2a 
 activity or inhibiting tau kinase activity in the brain . memantine , a low - to - moderate - affinity antagonist of nmda receptor , 
 which improves mental function and the quality of daily life of 
 individuals with moderate to severe ad [ 153 , 154 ] , reverses 
 the okadaic - acid - induced inhibition of pp2a activity and prevents 
 tau hyperphosphorylation in hippocampal slice cultures from adult 
 rats . the restoration of pp2a activity to normal level 
 by memantine also leads to restoration of the expression of map2 
 in the neuropil and a reversal of hyperphosphorylation and 
 accumulation of neurofilaments . wang 's group has demonstrated that 
 treatment of brain slices and rats with melatonin can restore pp2a 
 activity that is inhibited by okadaic acid or calyculin a and 
 reverse hyperphosphorylation of tau and neurofilament proteins as 
 well as cytotoxicities [ 156158 ] . melatonin also prevents 
 tau hyperphosphorylation and aggregation induced by overactivation 
 of gsk-3 or pka [ 131 , 159 ] . these are examples showing that 
 inhibition of dysregulation of protein 
 phosphorylation / dephosphorylation is a promising target to treat 
 ad . further investigation of new compounds that can inhibit 
 abnormal hyperphosphorylation of tau will likely provide new 
 treatments for ad . maps , microtubule - associated proteins ; mts , microtubules ; phfs , paired helical filaments ; nfts , neurofibrillary tangles .
studies during the last two decades have provided new insights 
 into the molecular mechanism of alzheimer 's disease ( ad ) . 
 one of 
 the milestone findings in ad research was the demonstration that 
 neurofibrillary degeneration characterized by tau pathology is 
 central to the pathogenesis of ad and other tauopathies and that 
 abnormal hyperphosphorylation of tau is pivotal to neurofibrillary 
 degeneration . 
 this article reviews the recent research advances in 
 tau pathology and the underlying dysregulation of the protein 
 phosphorylation / dephosphorylation system . 
 an updated model of the 
 mechanism of neurofibrillary degeneration is also presented , and a 
 promising therapeutic target to treat ad by correcting 
 dysregulation of protein phosphorylation / dephosphorylation is 
 discussed .