A Microtubules regulates activities from cell morphology to cytoskeletal

A platform of cytoskeletal
components regulates the morphology of neurons. Along these lines, proteins
that associates with important cytoskeletal segments such as microtubules can
alter directly both the morphology and physiology of neurons. Tau is a
microtubule associated protein (MAP) that behaves differently from other types
of proteins, its unfolded formation determines specificity in the function of
tau. Tau settles and stabilises neuronal microtubules under ordinary
physiological conditions, acting as blocks of Legos constantly securing the
morphology of neurons. However, under certain pathological circumstances, tau
undergo modifications that forms abnormal aggregates in neurofibrillary which
are harmful to neurons. This procedure happens in various neurological issues
known as tauopathy, the most regularly perceived tauopathy is Alzheimer’s
disease. The motivation behind this audit is to characterise the role of tau
protein under normal physiological condition in neuron and how tau contributes
to the development of Alzheimer’s disease.

Microtubules regulates activities
from cell morphology to cytoskeletal organisation, the crucial role of
microtubules requires a vast amount of MAP for regulation purposes (Maccioni
RB, Cambiazo V,2004). Tau, collectively known as MAP, is one of many that
modulates the association and interaction of microtubules, thence indirectly
maintaining normal cell function. From molecules of tubulin heterodimers to a cylindrical
microtubule that consists of ?and ? tubulin, the dynamics involved are purely supported
by MAP (Pryer NK.et al,2006). Tau contains two different way of regulating axonal
microtubule stability, isoform and differential phosphorylation. The human
brain contains six isoforms of tau that are uniquely generated by tau gene alternative
splicing (Pamela McMillan. Et al ,2008). The isoforms are composed of either
three or four tandem repeats with two projection terminal inserts on both sides,
C and N, responsible for interacting with microtubule(Pamela McMillan. Et al,
2008). A study executed by Maxime Derisbourg analyse the role of N-terminal
inserts in the stabilisation of microtubule (Derisbourg M. et al, 2015). Two specific
N-terminal inserts were truncated at Met11 and Gln24 respectively, biochemical
results show Gln-24 has the ability to bind and stabilise microtubules (Derisbourg
M. et al, 2015). This suggests the importance of isoforms in the role of direct
microtubule stabilisation by tau. Further, tandem repeats of isoforms act as
‘jaws’, flanking the turn edges of tubulin to promote bundle formation of
microtubules, enhancing the efficiency of microtubule nucleation and elongation
(Gustke N.et al, 2003), ultimately making suitable adjustments on microtubule
dynamics. Differential phosphorylation of tau is another predominant mechanism that
orchestrates axonal microtubule stability. Addition of phosphate by protein
kinase alters the molecular shape of tau (Fatma J. Ekinci and Thomas B. Shea,
2000), in turn possibility affecting the assembly of microtubules and
threatening stability. Lund ET respectively reported human tau phosphorylated
by protein kinase II actually promotes microtubule disassembly by
depolymerising tubulin structures, resulting in catastrophic disconnections
between tau and microtubule (Lund ET.et al , 2001). Furthermore, an increase in
levels of tau phosphorylation at Thr231 might result in increase of tau-tau
interaction, involving in neurodegenerative disease including Alzheimer’s (Akiko
Maruko-Otake. Et al,2016) (more will be discussed upon in latter part). It is
of critical importance that that amount of kinase and phosphatase are well
maintained so hyperphosphorylation will not result and tau could function
optimally. Recent article by Liu Fung, highlights tau dephosphorylation by
protein phosphate 5 can reduce the effect of abnormal hyperphosphorylation in Alzheimer’s(Liu
F. et al , 2005), suggesting how essential is tau in maintaining stable

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Specific areas of tau protein binds
to ? and ? tubulin of microtubules (Auréliane Elie. Et al,2015), likewise
tubulin molecules bind to motor kinesin and dynein. In fact apart from
stabilisation, tau protein indirectly takes part in axonal transport,
interfering with motor proteins. Evidences conducted by Dixit R shows that tau actually
relates to the light chain of motor protein kinesin-1 and the relationship
entirely depends on the phosphorylation state of tau (Dixit R.et al, 2008). For
instance, hyperphosphorylation can lead to the disassociation of tau from
microtubule, losing tau function in axonal transport (Lund ET.et al , 2001),
progressively leading to Alzheimer’s. This solidifies the importance of differential
phosphorylation of tau in modulating axonal transports by regulating the
binding to kinesin-1(Dixit R.et al, 2008).

Findings by numerous gene knockout
experiments support a new role of Tau protein in addition to its established
role in maintaining the stability of microtubule, tau is actually required for
the outgrowth of neurites. Knock-out mice with the loss of tau function was
tested against wild type mice and neurite extension rate was measured
respectively under different circumstances (Liu CW. Et al , 2000). The knock
out mice turns out to have a significantly smaller neurite extension rate by
approximately two folds when comparing to a wild type mice with normal tau function
(Liu CW. Et al, 2000). The redefined (knockout) mice demonstrated a postponed
neuronal development accompanied by the decrease in the neurite extension rate,
indicating the cooperative function of tau underlies the specific role of tau in
regulating the outgrowth of neurites. This implies hyperphosphorylation of tau
can lead to axonal degradation when tau stops stabilising microtubules, moving
one step closer to contracting Alzheimer’s (Liu F. et al, 2005).

Lastly, tau represents linker that
connects two cytoskeletal components together, acting as a bridge that cross
links filament networks and axonal microtubules via tubulin binding sites. For
instance, tau induces the co-alignment of growing microtubules along filaments
bundles, promoting guided polymerisation of microtubules and developing a
pattern of co-organising stability (Stuart Feinstein, Nichole Lapointe,
2017). Studies shown C- terminal part of tau has the ability more than
sufficient to physically link microtubule and actin filaments together,
stabilising microtubule(Stuart Feinstein, Nichole Lapointe, 2017), also
the proportion of microtubule associated with actin filaments greatly increases
under the influence of tau when comparing to microtubule-actin surface network
under fascin environment(Elie A. et al, 2015). An increase in the phosphate
level of tau can threaten the co –organising stability of microtubule, reducing
microtubule networks, developing Alzheimer’s eventually. The graph (Elie A.  et al, 2015) on the side sates how the
coordination of actin and microtubule by tau improves the formation microtubule
network and essentially perform a critical role in the context of neurones.


For the most part tau works
perfectly in neurons, maintaining the stability of microtubules and enabling a
speedy transport of axonal motor proteins. Furthermore, supporting the
outgrowth of neurites and crosslinking actin networks with microtubules.
However, dysfunction of tau was actually found to be pathological hallmark of Alzheimer’s
disease, abnormally phosphorylated tau aggregates in the neurofibrillary
tangles of the brain (Goran Šimi?. Et al,2016). In an actively function neuron,
microtubules forms and breaks up all the time. Tau’s binding capacity on
microtubule is always being adjusted by the addition or removal phosphate.
Enzymes including kinase add phosphate on tau protein, deliberately weakening
tau’s grip (Philip J Dolan and Gail VW Johnson, 2010). Different enzyme called
phosphateses catalysts in a vice versa reaction, de-phosphorylating tau to
increase tau’s capacity to grip (Liu F. et al , 2005). Alzheimer’s happen when the
phosphorylation process goes out of control and tau protein becomes hyperphosphorylated.
The brains of Alzheimer’s contain roughly 9 mol of phosphate while normal
brains contain only 2 mol (E. MandelkowJ. Et al , 1994). The staggering
increase of phosphate changes tau from a state of natively unfolded protein to
aggregates that ultimately forms neurofibrillary tangles in neurons. These type
of neurofibrillary tangles afflicts directly on a normal person’s brain, so
depending on the degree of tau compromising into neurofibrillary tangle,
actually correlates with the severity of dementia in a patient (Shaheen E
Lakhan, 2017). It is also equally fair to mention hyperphosphorylation can
result in the disassembly of microtubules and the reason behind the imbalance
of phosphate level is triggered by ?-amyloid peptide in Alzheimer’s, which in
turn develops senile plaques contributing to the aggregates in Alzheimer’s (P
Cras.et al , 2001).

Studies demonstrated there are at
least 39 identified phosphorylated sites in the tau molecule that associates to
the brain of Alzheimer’s patient when phosphorylation-dependent monoclonal
antibodies are introduced to the sample (Diane P. Hanger.et al, 2007). Phosphate
dependent Tau is actually the ‘culprit’ that is responsible for the development
of inclusions in Alzheimer’s, acting as a piece of domino that triggers a whole
series of downstream adverse effects.

It is widely recognised that tau
has the ability to support microtubules under most circumstances examples
include microtubule stability and axonal transport. However, under pathological
conditions, initial formations of fibrillary tangles from tau proteins promotes
the onset and evolution of Alzheimer’s.