Alzheimer’s affected brain tissue. The mechanisms that lead

Alzheimer’s disease and
the involvement of tau

Alzheimer’s disease (AD) is the most common cause of
dementia, and global prevalence is rising. In 2017, it is thought that
approximately 45 million people live with dementia, which is expected to
dramatically increase to over 130 million by 2050 (Guo, Noble and Hanger 2017). The disease is characterised
by progressive deterioration in cognitive function and behaviour (Reitz and Mayeux 2014), and the most common first
symptoms for patients are episodic memory impairments. There are different
variants that effects different processes dependent on the part of the brain
that pathogenesis has occurred, for example visual deterioration caused by
atrophy of the posterior region of the cerebral cortex (Ossenkoppele et al. 2015). AD brain tissue contains
(A?) peptide deposits in the form of diffuse and neuritic plaques, along with
hyperphosphorylated tau proteins that form neurofibrillary tangles (NFTs) (Reitz and Mayeux 2014). Both the NFTs containing tau
aggregates and the A? depositions, or amyloid plaques, provide the pathological
definition of Alzheimer’s disease (Boutajangout and Wisniewski 2014). The most toxic form of the A?
depositions are oligomeric forms, which are the primary causes of tau
hyperphosphorylation, thus causing NFTs (Boutajangout and Wisniewski 2014). These both cause pathogenesis to the
surrounding tissue leading to microgliosis, increased action of the microglial
cells, and loss of neurons, white matter and synapses in the affected brain
tissue. The mechanisms that lead to these abnormal changes still need to be
determined (Reitz and Mayeux 2014).

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Tau proteins in
normal neurons – more on microtubules and involvement in neurons

Tau proteins are one of the pathological causes of
Alzheimer’s disease. These microtubule- associated proteins stabilise
microtubules and promote assembly, assisting with the regulation of important
mechanisms such as cell division, intracellular transport and axon stability (Kadavath et al. 2015). Microtubules are composed of
tubulin heterodimers that polymerise to form protofilaments and associate to
form microtubules, which are stabilised and assembled by microtubule-associated
proteins such as tau. Drugs are being tested to reduce NFTs caused by
pathological changes in tau, such as derivatives of methylene blue used to
inhibit tau aggregation, and curcumin which inhibits Hsp90 which inhibits tau
degradation (Boutajangout and Wisniewski 2014). Problems that occur in Tau
proteins then cause neurodegenerative diseases such as AD (Kadavath et al. 2015), so it is important to
understand the roles of tau as there are currently few drugs available to treat
tauopathies (Guo et al. 2017).

There are six isoforms of tau in
the brain ranging in size from 352-441 amino acids, the differences in sizes
caused by exon 2 (29 amino acids) or exon 2 and 3 (58 amino acids) being
removed or not from the amino terminal (Boutajangout and Wisniewski 2014). Human tau is encoded by the
MAPT gene on chromosome 17. Tau expression is regulated, for example only the
shortest tau isoform is present in the foetal brain, whereas all 6 are present
in the adult human brain. The tau proteins have few hydrophobic residues making
it a hydrophilic protein, which can be separated into four major domains (shown
in figure 1); the N-terminal acidic projection domain, the proline-rich domain,
the microtubule binding domain and the C-terminal domain (Guo et al. 2017). The microtubule binding domain contains four
repeated motifs, of which the microtubules bind to for stabilisation. When
microtubules bind to tau the N-terminus and C-terminus, that are usually close
due to the ‘paperclip’ conformation, the termini move further apart, which also
happens when tau phosphorylation occurs. Dependent on the residues that are
involved in phosphorylation and there position depends on the change in conformation
of tau (Guo et al. 2017).

Kinases are involved in the phosphorylation of tau proteins,
for which inhibitors have been tested in clinical trials but have been
unsuccessful. Tau-tubulin kinase (TTBK) phosphorylates tau and tubulin, and has
two isoforms, TTBK1 and 2, with similar catalytic domains but different
non-catalytic domains (Ikezu and Ikezu 2014). Each isoform is present in
different parts of the body, TTBK1 in the central nervous system and TTBK2 in other
tissues around the body. The isoform that is responsible for the
phosphorylation of tau is therefore TTBK1, with phosphorylation mainly
occurring at Ser422 (Ikezu and Ikezu 2014).

proteins in Alzheimer’s disease

Assembly of tau in the wrong format causes insoluble aggregates
by tau forming paired helical filaments (figure) or straight filaments (Alavi Naini and Soussi-Yanicostas 2015) causing loss of activity at
synapses and death of neurons. Polymerisation of tau into filaments causes pathogenesis
due to

Because tau is a soluble protein, in normal brain tissue the
NFTs are unlikely to form

NFT formation is mainly characterised by tau
hyperphosphorylation, mono-ubiquination and conformational changes of tau.
Phosphorylated tau (pTau) present shows a problem in the balance between the
kinase and opposing phosphatase activity, or within the mechanisms to remove
pTau from the brain (Ikezu and Ikezu 2014).

Hyperphosphorylation occurs on the serine or threonine
residues, and is the main cause of NFTs in AD (Ikezu and Ikezu 2014).