The Role of Tau Protein in Normal Neurons and it’s
Involvement in the Development of Alzheimer’s Disease
Background
Alzheimer’s Disease (AD) is the most common form of
dementia, accounting for up to 80% of cases worldwide. Owing to
the world’s ageing population, the prevalence of the disease is
predicted to triple by the mid-century (Crous-Bou et al., 2017).
Characterized by progressive cognitive decline, AD results in the
impairment of memory and is often accompanied by the
deterioration of language skills; disorientation, personality
changes, depressed mood and in some cases psychosis (Tarawneh
and Holtzman, 2012). Consequently, AD can be described as one of
the largest global health challenges and the need for a cure is more 25μm
urgent than ever. The disease was first discovered over 100 years
ago by Dr. Alois Alzheimer, based on his 5-year observations of 51- Fig.1. The signature
year-old Auguste Deter. The histological analysis of the patient’s characteristics of the
brain tissue post-mortem uncovered the now known Alzheimer’s brain.
neuropathological hallmarks of AD (see Fig.1); distinctive amyloid Silver-staining of a histological
plaques and neurofibrillary tangles composed of Tau, hereinafter section of AD brain reveals
referred to as ‘Tau tangles’ (Hippius and Neundörfer, 2003). This neurofibrillary tangles of Tau
essay will focus on the latter, describing Tau and the principal protein (black arrows) and neuritic
contributions it makes under physiological conditions and how the plaques composed of the amyloid-
presence of Tau tangles is tightly linked to the neuronal beta (Aβ) protein (white arrow).
dysfunction observed in AD patients. Image adapted from Kanaan et al.
(2015)
Structure and Function of Tau Protein
Tau is a microtubule associated protein (MAP) that predominates in neurons. The
developmentally regulated Tau family constitutes six isoforms and, in the adult human brain, exist at
similar levels. The isoforms are generated by alternative splicing of the MAPT gene located on the
long arm of chromosome 17 (17q21) and are distinguished by the presence of up to two N-terminal
amino acid inserts, and either three (3R) or four (4R) C-terminal microtubule-binding domains
(Sotiropoulos et al., 2017). Through these domains, Tau serves its major biological function to
stabilize the microtubule network, thereby permitting cells to carry out multiple essential processes.
The microtubule binding domains are positively charged due to the presence of several lysine
residues and, as such, attract the negatively charged microtubules (Mietelska-Porowska et al., 2014).
Although the 3R isoforms will bind less tightly to microtubules than the 4R isoforms, once attached,
Tau proteins will promote their assembly. This is achieved through lowering the critical
concentration of tubulin required for polymerization and decreasing the frequency of catastrophes
by preventing tubulin dissociation from the microtubule ends (Best et al., 2019).
, Abnormal Hyperphosphorylation of Tau
The binding of Tau to microtubules is regulated by several post-translational modifications,
which are also pivotal for defining the localisation of its isoforms - the most well-established being
phosphorylation (Guo et al., 2017). The level of phosphorylation is modulated by Tau kinases, the
most important ones being cyclin-dependent kinase 5 (CDK5); glycogen-synthase kinase-3B (GSK-3B)
and cAMP-dependent protein kinase (PKA), and Tau phosphatases. But, under pathological
conditions, an imbalance in the activity of these enzymes (e.g. upregulation of CDK5) is considered
to lead to the hyperphosphorylation of Tau (Gong and Iqbal, 2008). In this state, Tau’s affinity for
microtubules is reduced as the positive charge of the microtubule binding domain becomes
neutralized. As a result, Tau dissociates from microtubules completely and begins to self-assemble.
The result is the formation of Tau tangles (see Fig.2). In its aggregated form Tau loses its stabilizing
abilities and, it follows that, a number of cellular processes that rely on microtubule function
become dysfunctional (Alonso et al., 2018).
Kinases
Neuronal
death
Phosphatases
Tau Tau oligomers Tau tangle
monomers aggregate assembly
Normal Tau Hyperphosphorylated Tau
stabilizes causes microtubule
microtubules depolymerization
Fig.2. The mechanism of Tau aggregation during the progression of AD.
In a healthy neuron, Tau binds and stabilizes microtubules. In pathological circumstances,
Tau becomes hyperphosphorylated as a result of increased kinase (transfer of phosphate
groups) and decreased phosphatase (remove phosphate groups) activity. When this
happens, microtubules begin to disassemble leading to the aggregation of soluble
hyperphosphorylated monomers into Tau oligomers, and further into insoluble Tau tangles.
Tau tangles pose a significant burden to neurons by reducing normal neuronal functioning,
causing toxicity and ultimately, their death.
Adapted from Barron et al. (2017)
Roles of Tau and its Implications in AD
The process of neurite extension – a requirement for neuron maturation – is one that
depends on microtubule dynamics. Studies have shown that when the expression of Tau is
suppressed, neurite outgrowth is not observed (Johnson and Stoothoff, 2004). This indicates a key
role of Tau in the generation of axonal morphology and, ultimately, neuronal development.
Although it hasn’t been well-established, it is presumed that Tau forms cross-bridges that allow the
