PET imaging of tau proteins

Tau (tubulin-associated unit) proteins include six isoforms produced by alternative mRNA splicing of the MAPT (microtubule-associated protein tau) gene. Tau proteins are natively unfolded and contain 352-441 amino acids, having up to 85 potential phosphorylation sites (serine, threonine and tyrosine). The relative activities of kinases and phosphatases, and conformation of the tau protein itself, determine the phosphorylation status. Tau proteins are involved in microtubule assembly and stabilization, and in regulation of motor-driven intracellular transport in neuronal axons. Increased phosphorylation leads to decreased binding to microtubules and subsequently disruption of microtubules. In addition to phosphorylation, tau proteins are regulated by also other post-translational modification such as glycation, nitration, acetylation, and proteolytic truncation.

Tau proteins are widely expressed in the central and peripheral nervous system, especially in neuronal axons, but also in the kidneys and lungs. Hyperphosphorylated tau proteins accumulate in the somatodendritic compartments of neurons, forming aggregates and eventually neurofibrillary tangles. These neurofibrillary tangles in the brain are found in several neurodegenerative diseases (tauopathies, proteinopathies), including Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP). In AD the tau proteins are surrounded by the more abundantly present amyloid β protein.

PET tracers

Development of PET tracers for tau protein aggregates has been hindered by the post-transitional modifications and resulting multiple 3D structures that the tau proteins can adopt in the aggregates. Another problem is the abundance of amyloid β in the aggregates; therefore most of the tau tracers are developed for other tauopathies than AD where amyloid β deposits are not present. Tracer must also be able to pass the blood-brain barrier, and show low or no specificity to α-synuclein.

Despite of the problems, several PET tracers targeting abnormal conformations of the tau proteins have been developed (Villemagne et al., 2015), including [18F]THK523, [18F]THK5105, [18F]THK5117, [18F]THK5351, [18F]T807 (also known as [18F]AV-1451 and Flortaucipir), [18F]T808, and [11C]PBB3 and its 18F-labelled versions.

Tracer affinities to different tau aggregate types may vary, and therefore certain tracers may be better suited for certain tauopathies (Bischof et al., 2017). [18F]THK523, [18F]THK5105, [18F]THK5117, and [18F]THK5351 are selective to the AD tau aggregates, and do not bind to α-synuclein deposits. [18F]THK5351 has lower nonspecific uptake in the white matter, and faster kinetics than the other THK tracers. However, [18F]THK5351 binds to MAO-B, which may limit its usability in studies of cortex and basal ganglia (Bischof et al., 2017). In vivo [18F]THK5117 uptake in the human brain did not correlate with biopsy verified tau pathology (Leinonen et al., 2018).

[18F]T807 and [18F]T808 seem to have good selectivity for AD and non-AD tau aggregates over amyloid β. However, [18F]T807 binds also to MAO-A and MAO-B with high affinity (Barrio, 2018).

[11C]PBB3 is selective for a relatively broad range of tau structures, but it may have some specificity to α-synuclein deposits, too (Bischof et al., 2017).

Additionally, amyloid β tracer [18F]FDDNP binds to both extracellular amyloid β plaques and the intracellular neurofibrillary tangles.


See also:



References:

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Created at: 2015-08-17
Updated at: 2018-06-12
Written by: Vesa Oikonen