Tauopathies are a heterogeneous group of neurodegenerative diseases characterized by abnormal metabolism of misfolded τ (tau) proteins leading to intracellular accumulation and formation of neurofibrillary tangles (NFT). These neurofibrillary tangles are deposited in the cytosol of neurons and glial cells.
Terminology
It should be noted that some texts 2 define tauopathies as a disease characterized by mutations in the τ protein gene itself. If such a strict definition is used, even though the histopathological hallmark of Alzheimer disease is the presence of numerous neurofibrillary tangles (which are also formed by τ proteins), it still would not be strictly a tauopathy, as no defect in the tau protein gene has been identified. Thus, it is referred to as a secondary tauopathy as β-amyloid accumulation is considered the primary pathology 5.
Pathology
Tauopathies are the result of aggregation and precipitation of misfolded τ proteins that normally stabilize neural microtubules. These aggregates form neurofibrillary tangles that in turn lead to neuronal toxicity and degeneration. Misfolded τ proteins from two distinct aggregates: three repeat (3R) and four repeat (4R) which variably present in different diseases 5.
Since the discovery of the glymphatic pathway and the importance of this in the normal physiological clearance of extracellular solutes including beta-amyloid, there is also the possibility of reduced clearance, in addition to abnormal metabolism, as the underpinning of some tauopathies including chronic traumatic encephalopathy 4.
Examples of tauopathies include 3:
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primary tauopathies
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4R tauopathies
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3R tauopathies
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mixed 4R/3R tauopathies
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secondary tauopathies
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secondary to amyloid deposition (mixed 4R/3R tauopathies)
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secondary to repeated trauma (mixed 4R/3R tauopathies)
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secondary to autoimmune response
anti-IgLON5 autoimmune encephalitis
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