656 Current Alzheimer Research, 2010, 7, 656-664
1567-2050/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
Tau in Alzheimer Disease and Related Tauopathies
K. Iqbal*, F. Liu, C.-X. Gong and I. Grundke-Iqbal
Department of Neurochemistry; New York State Institute for Basic Research; In Developmental Disabilities; Staten Is-
land, New York; USA
Abstract: Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are
MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into
microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phos-
phoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2–3 moles phos-
phate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease
(AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphos-
phorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neu-
rofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia
but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from tran-
siently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and
(2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike
normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the
tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia ap-
parently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distin-
guishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric
state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promis-
ing therapeutic target for AD and related tauopathies.
Keywords: Microtubule associated proteins, hyperphosphorylation of tau, microtubule assembly, neurofibrillary tangles, paired
helical filaments, tau truncation.
of a normal mature neuron. The other two neuronal MAPs
are MAP1 and MAP2. Tau is found as six molecular iso-
forms in human brain . These isoforms are coded by a
single gene on chromosome 17 and are generated by alterna-
tive splicing of its pre-mRNA . To date, the only estab-
lished function of tau, a phosphoprotein, is the promotion of
the assembly of tubulin into microtubules and stabilization of
their structure .
Tau is the major microtubule associated protein (MAP)
rodegenerative diseases, called tauopathies, tau protein is
abnormally hyperphosphorylated and aggregated into bun-
dles of filaments . In AD brain this tau pathology is seen
as intraneuronal neurofibrillary tangles of paired helical
filaments (PHF) sometimes admixed with straight filaments
(SF). Aggregates of abnormally hyperphosphorylated fila-
ments are also seen in dystrophic neurites surrounding the ?-
amyloid plaque core, and in the neuropil as neuropil threads
. Neurofibrillary degeneration of abnormally hyperphos-
phorylated tau is apparently required for the clinical expres-
sion of AD and related tauopathies [6-8]. Thus, understan
In Alzheimer disease (AD) and a family of related neu-
*Address correspondence to this author at the Department of Neurochemis-
try; New York State Institute for Basic Research in Developmental Disabili-
ties; 1050 Forest Hill Road, Staten Island, New York 10314-6399; USA;
Tel.: 718-494-5259; Fax: 718-494-1080;
ding the etiopathogenesis of this pivotal and hallmark lesion
of AD and related tauopathies is critical to developing ra-
tional therapeutic treatments of these human CNS diseases.
Studies on the role of tau in neurodegeneration and therapeu-
tic targets based on this pathology have been the subject of
several recent reviews by us and others [9-17]. This article
discusses the relationship between normal and pathological
taus found in AD and related tauopathies.
STRUCTURE AND FUNCTION OF NORMAL BRAIN
mRNA results in six molecular isoforms of the protein .
These six tau isoforms differ in containing three (3R taus) or
four (4R taus) microtubule binding repeats (R) of 31–32
amino acids in the carboxy terminal half and one (1N), two
(2N), or zero (0N) amino terminal inserts of 29 amino acids
each; the extra repeat in 4R tau is the second repeat (R2) of
4R taus. This alternative splicing of tau pre-mRNA results in
the expression of three 3R taus (0N3R, 1N3R, and 2N3R)
and three 4R taus (0N4R, 1N4R, and 2N4R). The 2N4R tau
is the largest size human brain tau with a total of 441 amino
acids (tau441) in length. The smallest size tau isoform, which
lacks both the two amino terminal inserts and the extra mi-
crotubule binding repeat (0N3R; tau352), is the only form that
is expressed in fetal human brain. Tau has little secondary
structure; it is mostly random coil with ? structure in the
second and third microtubule binding repeats.
In human brain the alternative splicing of the tau pre-
Tau in Alzheimer Disease and Related Tauopathies Current Alzheimer Research, 2010, Vol. 7, No. 8 657
microtubules and helps stabilize their structure . Like
MAP1 and MAP2, tau is a phosphoprotein and its biological
activity is regulated by the degree of its phosphorylation [18-
20]. Normal brain tau contains 2–3 moles of phosphate per
mole of the protein , which appears to be optimal for its
interaction with tubulin and the promotion of microtubule
assembly. In addition to phosphorylation, the alternative
splicing also affects the biological activity of tau. Both the
extra repeat (Repeat 2) in the 4R taus and the amino terminal
inserts (N1 and N2) enhance the binding of tau to tubulin,
which makes 2N4R tau (tau441), and 0N3Rtau (tau352, the
fetal tau) the relatively most and the least effective in pro-
moting microtubule assembly [21, 22]. All six isoforms of
tau are highly hydrophilic and are, thus, soluble and heat
In a normal mature neuron tubulin is present in over ten-
fold excess of tau. The neuronal concentration of tau is ~2
μM [23, 24] and it binds to microtubules at a Kd of ~100 nM
, and thus practically all tau is likely to be microtubule
bound in the cell. In cultured cells overexpression of tau can
cause microtubule bundling. However, neither in AD nor in
any related tauopathy such a situation has been reported.
Tau interacts with tubulin and promotes its assembly into
PATHOLOGICAL FORMS AND STATES OF TAU
Abnormal Hyperphosphorylation and Oligomerization of
phorylated tau not only occurs in AD brain but is also seen in
a family of related neurodegenerative diseases, called
tauopathies, such as fronto-temporal dementia with Parkin-
sonism linked to chromosome 17 (FTDP-17) caused by tau
mutations, Pick disease, corticobasal degeneration, dementia
pugilistica, and progressive supranuclear palsy. In every one
of these tauopathies the neurofibrillary changes are made up
of abnormally hyperphosphorylated tau and their occurrence
in the neocortex is associated with dementia. In frontotempo-
ral dementia with Parkinsonism-linked to chromosome 17
and tau pathology (FTDP-17-tau), several missense muta-
tions in tau cosegregate with the disease [26-28]. Four of
these missense mutations, G272V, P301L, V337M, and
R406W, which have been most studied to date, make tau a
preferable substrate for abnormal hyperphosphorylation in
vitro . The neurofibrillary degeneration of the Alzheimer
type is primarily seen in human neurodegenerative disorders.
To date, in aged and in cognitively impaired animals the
neurofibrillary degeneration of abnormally hyperphosphory-
lated tau has been found only sparsely.
Neurofibrillary degeneration of abnormally hyperphos-
tauopathy, the tau pathology is made up of the abnormally
hyperphosphorylated protein. In AD brain all of the six tau
isoforms are hyperphosphorylated and aggregated into PHF
[4, 29-33]. While conformational changes [34-36] and trun-
cation of tau [37-39] following its hyperphosphorylation
have been reported in AD, the most established and the
most compelling cause of dysfunctional tau in AD and re-
lated tauopathies is the abnormal hyperphosphorylation of
this protein [4, 20, 31].
To date, not only in AD but also in every known human
recovered in 200,000 x g cytosol, from AD brain this protein
is recovered in three major states, i.e. soluble, oligomeric,
and fibrillized [19, 31, 41]. There is at least as much normal
cytosolic tau in AD brain as in normal aged brain but the
level of total tau in the former is four to eight fold higher and
this increase is solely in the form of the abnormally hyper-
phosphorylated protein . As much as 40% of the tau
from AD brain is non-fibrillized but oligomeric and sedi-
ments at 200,000 x g . These tau oligomers isolated from
AD brain, as 27,000 x g to 200,000 x g fraction, are made up
of both abnormally hyperphosphorylated and non-hyperpho-
sphorylated taus, and the two can be separated by phos-
phocellulose chromatography [19, 31]. Up until recently 
this oligomeric tau was referred to as cytosolic tau, amor-
phous tau, and sedimentable cytosolic abnormally hyper-
phosphorylated tau [19, 20, 31, 41, 43-47]. The abnormally
hyperphosphorylated tau purified from the oligomers is three
to four fold more hyperphosphorylated as the non-hyper-
phosphorylated/normal tau .
While in normal brain almost all tau is soluble and is
Neurotoxic State of Tau
mote assembly and to maintain structure of microtubules .
The tau polymerized into neurofibrillary tangles is appar-
ently inert and neither binds to tubulin nor promotes its as-
sembly into microtubules [45, 48, 49]. As much as 40% of
the abnormally hyperphosphorylated tau in AD brain is pre-
sent in the cytosol and not polymerized into paired helical
filaments/neurofibrillary tangles [19, 31, 41]. The AD cyto-
solic abnormally hyperphosphorylated tau (AD P-tau) does
not bind to tubulin and promote microtubule assembly, but
instead it inhibits assembly and disrupts microtubules Fig.
(1) [20, 50, 51]. This toxic property of the pathological tau
involves the sequestration of normal tau by the diseased pro-
tein [20, 44]. The AD P-tau also sequesters the other two
major neuronal microtubule associated proteins MAP1 A/B
and MAP2 . This toxic behavior of the AD P-tau appears
to be solely due to its abnormal hyperphosphorylation be-
cause dephosphorylation of diseased tau converts it into a
normal-like protein [20, 50-52].
The inhibitory activity of the non-fibrillized abnormally
hyperphosphorylated tau has been confirmed in yeast, droso-
phila, and in mouse models that express human brain tau.
The expression of the longest human brain tau (2N4Rtau) in
yeast produces pathological phosphoepitopes, assumes a
pathological conformation, and forms aggregates. These
processes are modulated by yeast kinases Mds1 and Pho85,
orthologues of GSK-3? and cdk5 [53, 54]. In yeast tau ag-
gregates more when it is more phosphorylated, the mobility
in SDS-PAGE is slower with increased phosphorylation, and
hyperphosphorylated tau isolated from the stably transfected
yeast is able to assemble into filaments, and is able to nucle-
ate the assembly of the normal non-phosphorylated tau.
These yeast studies, like those carried out previously using
AD P-tau, suggest that the hyperphosphorylated tau works as
a nucleation factor that initiates and promotes the aggrega-
tion of tau [44, 55].
In wild-type human tau- and mutated human tau-
transgenic drosophila, the accumulation of the abnormally
Two major known functions of tau are its ability to pro-
658 Current Alzheimer Research, 2010, Vol. 7, No. 8 Iqbal et al.
Fig. (1). A schematic representation of various pathological states of tau originating from normal brain tau and associated loss of
normal and gain of toxic functions.
Normal brain tau, which has a stoichiometry of 2–3 moles phosphate/mole of the protein, stimulates assembly of tubulin and stabilizes the
structure of microtubules produced. During development, anesthesia as well as hypothermia, such as during hibernation, tau is transiently
hyperphosphorylated. During development the level of brain tubulin is >4 mg/ml, the critical concentration required for its self-assembly into
microtubules and the role of tau for this function is less critical. The hyperphosphorylation of tau during anesthesia and hypothermia, how-
ever, leads to a decrease in microtubule network and the associated functions.
In AD brain a phosphorylation/dephosphorylation imbalance caused apparently by a decrease in protein phosphatase-2A activity leads to
abnormal hyperphosphorylation of tau. This AD P-tau on one hand sequesters normal MAPs from microtubules and causes inhibition and
disruption of microtubules. On the other hand, while the binding of AD P-tau to MAP1 or MAP2 results in amorphous aggregates, the bind-
ing to normal tau forms oligomers. Unlike normal tau, which is highly soluble, the tau oligomers formed with AD P-tau can be sedimented at
200,000 x g and self-assemble into PHF/SF in the form of neurofibrillary tangles.
phosphorylated tau in the absence of its fibrillization into
neurofibrillary tangles leads to neurodegeneration . In a
P301L tau inducible transgenic mouse model, cognitive im-
provement was observed when expression of human tau,
which became abnormally hyperphosphorylated, was sup-
pressed although neurofibrillary tangles continued to form,
suggesting that the accumulation of the cytosolic abnormally
hyperphosphorylated tau, and not its aggregation, was appar-
ently involved in behavioral impairment in these animals
. Reduction of soluble A? and soluble abnormally hy-
perphosphorylated tau, but not soluble A? alone, was found
to ameliorate cognitive decline in 3xTg mice that express
both plaque and tangle pathology . Furthermore, in vitro
dephosphorylation of neurofibrillary tangles disaggregates
Tau in Alzheimer Disease and Related Tauopathies Current Alzheimer Research, 2010, Vol. 7, No. 8 659
filaments and, as a result, the tau released behaves like nor-
mal protein in promoting microtubule assembly . Thus,
two characteristics of AD abnormally hyperphosphorylated
tau are (1) that it sequesters normal MAPs and disrupts mi-
crotubules and (2) that it self-assembles into PHF/SF.
In a recent study methylthioninium chloride (methylene
blue dye) has been found to disaggregate PHF in vitro, re-
duce the number of tau aggregates in tau transgenic mice,
and show significant inhibition of cognitive impairment in a
PHASE II double blind clinical trial in AD patients [59, 60].
Whether disaggregation of pathological aggregates of tau
with methylthioninium chloride results also in its dephos-
phorylation and removal remains to be studied.
Transient and Reversible Hyperphosphorylation of Tau
level as in AD, is not only associated with the disease as in
tauopathies, but is also employed by the neuron to down
regulate its activity transiently and reversibly where required
Fig. (1). For instance, during development the level of tubu-
lin in the brain is at its highest, i.e., almost 33% of total cyto-
solic protein, which is almost 1.5-fold the critical concentra-
tion of 4 mg/ml tubulin required for its polymerization into
microtubules . Probably to avoid microtubule bundling,
the fetal tau is transiently hyperphosphorylated during devel-
opment. However, the level of hyperphosphorylation of tau
in fetal brain is far less than that seen in AD brain. Similarly,
anesthesia and hypothermia induced by hibernation in ani-
mals results in transient hyperphosphorylation of tau [62-65].
The molecular mechanism of the transient hyperphosphory-
lation of tau observed during development is, at present, not
understood. However, during hypothermia the activity of
protein phosphatase-2A (PP-2A), the major brain phos-
phoseryl/phosphothreonyl protein phosphatase activity is
transiently and reversibly reduced and is believed to cause
the hyperphosphorylation of tau [62, 63]. In AD and Down
syndrome, the decrease in brain PP-2A activity apparently
involves different molecular mechanisms, and occurs in a
non-transient and irreversible manner [66-68]. It is the non-
reversible nature of the abnormal hyperphosphorylation of
tau in AD, Down syndrome, and related tauopathies which
results in an involuntary slowing down of neuronal activity
and a consequent chronic progressive neurodegeneration and
its clinical phenotype, the dementia.
Hyperphosphorylation of tau, though not to the same
Fibrillization of Abnormally Hyperphosphorylated Tau
regions that are not conducive for intermolecular hydropho-
bic association . The ?-structure in tau is concentrated
only in repeats R2 and R3 which can self-assemble into
filaments  and co-assemble with heparin . Both the
amino terminal and the carboxy terminal flanking regions to
the microtubule binding repeats in normal tau appear to in-
hibit its self-aggregation into filaments and on AD type ab-
normal hyperphosphorylation, i.e., the phosphorylation of
the amino terminal and the carboxy terminal flanking re-
gions, this inhibition is eliminated, resulting in the formation
of tangles of PHF/SF [21, 46]. The co-assembly of tau with
polyanions such as heparin, heparin sulfate [72-75], tRNA
Tau has long stretches of positively or negatively charged
, or polyglutamate  appears to involve a mechanism
different from what is seen in AD and in tauopathies. The
polyanion-induced assembly of tau is very slow and does not
result either in the lateral association of filaments into tan-
gles nor the formation of any protofilaments seen in AD
PHF. Furthermore, unlike AD and related tauopathies and
transgenic animal models, the in vitro polyanions-induced
assembly of tau into filaments is inhibited and not promoted
by phosphorylation .
lated from AD brain results in their dissociation and disag-
gregation, and the dephosphorylated tau released behaves
like normal tau in promoting microtubule assembly in vitro
. Similarly, dephosphorylation of AD cytosolic abnor-
mally hyperphosphorylated tau with PP-2A inhibits its abil-
ity to self-aggregate into PHF/SF, sequester normal tau, and
inhibit microtubule assembly in vitro, and rephosphorylation
of the PP-2A-AD P-tau by several combinations of protein
kinases restores all of its above pathological properties [47,
Dephosphorylation of PHF/neurofibrillary tangles iso-
sistant to proteolysis by the calcium activated neutral prote-
ase [51, 52] and turnover of hyperphosphorylated tau is sev-
eral fold slower than the normal tau . Most likely it is
because of this reason that the levels of tau are several-fold
increased in AD [12, 24]. Some increase in tau level in AD
brain can also result from the activation of p70 S6 kinase
which upregulates the translation of tau [80, 81]. It is likely
that to neutralize the ability of AD P-tau to sequester normal
MAPs and cause disassembly of microtubules, the affected
neurons promote the self-assembly of the abnormal tau into
tangles of PHF. The fact that the tangle-bearing neurons
seem to survive many years  and that in AD brain the
decrease in microtubule density was unrelated to PHFs ac-
cumulation  is consistent with such a self-defense role of
the formation of tangles. Employing an inducible transgenic
mouse model that expressed human four-repeat tau with the
P301L mutation, Santacruz and colleagues  found that
the cognitive deficiencies correlate with the appearance of
soluble hyperphosphorylated tau. In this model when tau
expression was turned off, there was no clearance of the po-
lymerized tau, soluble phosphotau decreased, and there was
improvement in cognition, suggesting that the polymerized
tau was not sufficient to cause cognitive decline or neuronal
cell death. Andorfer et al.  showed that in human tau
transgenic mice, while there was widespread neurodegenera-
tion, the PHF-containing neurons, however, appeared
“healthy” in terms of nuclear morphology, suggesting that
the polymerization of hyperphosphorylated tau into fibrils
was probably neuroprotective . Thus, all these studies
taken together demonstrate the pivotal involvement of ab-
normal hyperphosphorylation in neurofibrillary degeneration
and the disruptive properties to the microtubule network of
the cytosolic abnormally hyperphosphorylated tau, whereas
AD P-tau polymer remains inert Fig. (1).
The abnormal hyperphosphorylation of tau makes it re-
Effect of Hyperphosphorylated Tau on Rough Endo-
plasmic Reticulum and Golgi
dendritic compartment as in the axon . In the somato-
There is approximately as much tau in the somato-
660 Current Alzheimer Research, 2010, Vol. 7, No. 8 Iqbal et al.
dendritic compartment tau is associated with rough endo-
plasmic reticulum and Golgi apparatus [19, 31, 85]. The ab-
normal hyperphosphorylation of tau and its accumulation in
the somato-dendritic compartment in AD might have been
responsible for the morphological alterations of the RER and
the Golgi apparatus and the abnormal N-glycosylation of tau
in AD [86-88]. In AD brain abnormally hyperphosphorylated
tau, in addition to forming neurofibrillary tangles, is associ-
ated with granulovacuolar changes [4, 89-91]. Overexpres-
sion of tau, which results in its hyperphosphorylation, has
been found to induce fragmentation of Golgi both in neu-
ronal cultures and in neurons in JNPL3 P301L tau transgenic
mice . In P301S tau transgenic mice, which show ab-
normal hyperphosphorylation of tau, a selective decrease in
mitochondria and RER has been observed . The chronic
accumulation of the hyperphosphorylated tau as a misfolded
protein in the ER could cause neurodegeneration due to pro-
tracted ER stress . Hyperphosphorylation of tau might
also be involved in neurodegeneration through alterations of
RER and Golgi and a consequent reduction in RER and mi-
Truncation of Tau
tional changes and cleavage of tau have also been implicated
in the pathogenesis of AD [34, 37, 38, 94]. The hyperphos-
phorylation of tau has been found to precede both conforma-
tional changes and cleavage of this protein . Truncation
of tau might make it a more favorable substrate for abnormal
hyperphosphorylation. Transgenic rats expressing human tau
truncated both N- and C-terminally tau151–391 show a marked
neurofibrillary degeneration of abnormally hyperphosphory-
lated tau . Hyperphosphorylation is known to produce
conformational changes in a protein. The late appearance and
low abundance of cleaved tau in neurofibrillary tangles
probably represent little more than the unsuccessful attempts
of the affected neuron to turn over the pathological aggre-
In addition to abnormal hyperphosphorylation, conforma-
Proteolysis of Abnormally Hyperphosphorylated Tau
change in the expression of tau mRNA in AD brain .
Thus, the increase in tau level observed in AD brain is
probably mostly due to a decrease in its turnover caused by
the hyperphosphorylation [51, 79, 97]. The AD abnormal
hyperphosphorylation of tau (AD P-tau) makes tau resistant
to both calcium activated neutral proteases, calpains, and its
degradation by the ubiquitin-proteasome pathway. Unlike
normal tau, the AD hyperphosphorylated tau is resistant to
proteolysis by calpains .
In situ hybridization studies have revealed no significant
brillary tangles, tau becomes polyubiquitinated [19, 41, 98-
105]. However, the ubiquitination of the abnormally hyper-
phosphorylated tau in neurofibrillary tangles apparently does
not lead to its clearance by digestion in the proteasome. This
could partly be due to a faster rate of accumulation of the
ubiquitinated phosphotau than the ability of the proteasomes
of the degenerating neurons to digest it. Inhibition of the
proteasome by its inhibitor, lactacystin, increases accumula-
tion of both normal and hyperphosphorylated taus in rats
Subsequent to its hyperphosphorylation in AD neurofi-
. Inhibition of the proteasome with its inhibitor, MG-
132, in cultured oligodendrocytes causes ubiquitination and
aggregation of tau . An in vivo cause of impaired pro-
teasome might be the occurrence, in the tangle-bearing neu-
rons, of the one frame-shift mutation of ubiquitin (UBB+1)
which inhibits the proteasome activity . Another cause
of the proteasome inhibition could be the increased level of
BAG-1, an Hsp70/Hsc70 binding partner in the degenerating
neurons. BAG-1 has been shown to inhibit degradation of
tau by the 20S proteasome without affecting the ubiquitina-
tion of tau .
Overexpression of Hsp70 which interacts with the heat-
shock cognate (Hsc) 70-interacting protein (CHIP), a ubiq-
uitin ligase, causes a reduction of tau in transgenic mice
. In AD brain levels of both CHIP and Hsp70 are in-
creased and the level of the former is inversely proportional
to that of sarkosyl-insoluble tau . The increase in CHIP
might be protective in the early stages of AD. Interestingly,
chronic administration of lithium, a known GSK-3? inhibi-
tor, has been reported to decrease the tau lesions by promot-
ing their ubiquitination in a tau transgenic mouse model
. Protein kinase B, Akt, which can hyperphosphorylate
tau both directly and indirectly through GSK-3? and
PAR1/MARK2, has been reported to prevent CHIP-induced
tau ubiquitination and its subsequent proteolysis either by
regulating Hsp90/CHIP complex directly or by competing as
a client protein with tau for binding .
Tau Mutations Found in Frontotemporal Dementia Pro-
mote Abnormal Hyperphosphorylation
increase in 4-R:3-R tau ratio or in missense mutations in the
protein. Both 4-repeat tau and the mutated protein are more
easily abnormally hyperphosphorylated than the normal
wild-type protein [21, 114]. Four of these missense muta-
tions, G272V, P301L, V337M, and R406W, which have
been most extensively studied to date, make tau a more fa-
vorable substrate than the wild-type protein for abnormal
hyperphosphorylation by brain protein kinases in vitro .
These mutated taus become hyperphosphorylated at a faster
rate and self-aggregate into filaments more readily, i.e., at a
phosphorylation stoichiometry of 4–6 as compared to ten or
more in the case of the wild-type protein. These faster kinet-
ics of the hyperphosphorylation of the mutated tau might
explain a relatively early onset, severity, and autosomal
dominance of the disease in the inherited FTDP-17 cases.
The six human brain tau isoforms are differentially se-
questered by AD P-tau in vitro . The association of AD
P-tau to normal human brain recombinant taus is
2N4Rtau>1N4Rtau>0N4Rtau and 2N3Rtau>1N3Rtau>0N-
3Rtau, and 2N4Rtau>2N3Rtau. AD P-tau also inhibits the
assembly and disrupts microtubules pre-assembled with each
tau isoform with an efficiency which corresponds directly to
the degree of interaction with these isoforms. In vitro hyper-
phosphorylation of recombinant tau converts it into an AD P-
tau-like state in sequestering normal tau and inhibiting mi-
crotubule assembly. The preferential sequestration of 4R taus
and taus with amino terminal inserts explains both (i) why
fetal tau (ON3Rtau) is protected from Alzheimer neurofibril-
lary pathology and (ii) why intronic mutations seen in certain
Tau mutations, which cause FTDP-17, result either in
Tau in Alzheimer Disease and Related Tauopathies Current Alzheimer Research, 2010, Vol. 7, No. 8 661
inherited cases of FTDP-17, which result in alternate splicing
of tau mRNA and consequently an increase in 4R:3R ratio,
lead to neurofibrillary degeneration and the disease. In vitro,
at a phosphorylation stoichiometry of 4 and above, the hy-
perphosphorylated tau sequesters normal tau, whereas it re-
quires a stoichiometry of 10 or more to self-aggregate into
filaments [21, 45, 46]. On aggregation into filaments, tau
loses its ability to sequester normal tau. Furthermore, AD P-
tau, but not PHF, inhibits regeneration of microtubule net-
work in detergent-extracted PC12 cells, indicating that the
formation of filaments might be initiated as a self-defense
response by the affected neurons [45, 50]. Opposite to
FTDP-17, in Pick disease and in Down syndrome (DS) the
tau 3R:4R ratio is very much increased [115-117]. Since the
activity of 3R tau is lesser than of 4R tau in binding to tubu-
lin/microtubules, the unbound 3R tau becomes abnormally
hyperphosphorylated because free tau is a more favorable
substrate than tau on microtubules for phosphorylation .
seen in AD is different from the normal and from the tran-
sient hyperphosphorylation of this protein that occurs during
development, anesthesia, or hypothermia. The cytosolic AD
abnormally hyperphosphorylated tau (AD P-tau) is sedimen-
table/oligomeric, and probably causes neurodegeneration by
sequestering normal MAPs and disrupting microtubule net-
work. Tau mutations found in frontotemporal dementia may
cause neurodegeneration through promoting abnormal hy-
perphosphorylation of tau. AD P-tau self-assembles into
PHF/SF, forming neurofibrillary tangles. Tau truncation
found in AD brain promotes its self-assembly into PHF/SF.
Unlike AD P-tau, PHF/SF neither sequester normal MAPs
nor disrupt microtubules. Thus, inhibition of abnormal hy-
perphosphorylation of tau offers a promising therapeutic
target for AD and related tauopathies.
In conclusion, the abnormal hyperphosphorylation of tau
tance. Dr. Ezzat El-Akkad helped prepare Fig. (1). Studies in
our laboratories were supported in part by the New York
State Office of Mental Retardation and Developmental Dis-
abilities; NIH grants AG019158, AG028538, and AG27429;
and Alzheimer’s Association (Chicago, IL) grants IIRG-00-
2002, HRG-05-13095, and NIRG-08-91126.
We are grateful to Ms. Janet Murphy for secretarial assis-
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Received: November 20, 2009 Revised: January 01, 2010 Accepted: January 02, 2010