03/08/2018

Short Article on Alzheimer's Disease: #5 Tau Aggregation and Propagation

The axons of neurons are made of microtubules that serve as tracks for neuronal transport. They are formed from tubulin and are widely believed to be stabilised by a protein called tau. Post-translational modifications of tau (e.g. phosphorylation) alter its structure and conformation and as a result impact its ability to bind to microtubules. In Alzheimer’s disease, several factors will promote these changes and the resulting modified tau proteins will start to self-aggregate into neurofibrillary tangles, which are thought to contribute to the degeneration of neurons.

Tau Aggregation

Structural biology studies have shown that the main components of neurofibrillary tangles in AD are paired helical and straight filaments and are mostly composed of abnormally hyperphosphorylated tau proteins.[1] The tangles form by aggregation of monomeric hyperphosphorylated tau into higher-order molecular species and assemble first as dimers then oligomers followed by (Paired Helical Filaments) PHFs and finally into the characteristic neurofibrillary tangles of AD.

Tau Propagation
Recent evidences suggest that tau aggregates are formed first in a small number of brain cells and then propagate to other neuroanatomically connected regions via a “prion-like mechanism” [2]. The idea is that tau “seeds” or fibrils, when entering adjacent cells, might recruit endogenous tau and seed further aggregation and as a result spread pathology. This idea is gaining popularity and several studies have demonstrated its occurrence in cell culture and animal studies.[3]

StressMarq Biosciences has recently released the first commercially available Active Tau Monomers and Pre-Formed Fibrils (PFFs) to facilitate research on tau aggregation. This follows the recent launch of its first active human and mouse alpha-synuclein monomers and pre-formed fibrils for Parkinson's research. All products are available in the UK and Ireland from Newmarket Scientific.











The new active tau proteins are available as two sets of monomers and PFFs:
  • from a full-length tau protein (2N4R or Tau-441) with a P301S mutation encoded by exon 10 to prevent microtubule assembly [4]
Active Human Recombinant Tau441 (2N4R), P301S mutant Protein Monomer (Cat. No. SPR-327)
Active Human Recombinant Tau441 (2N4R), P301S mutant Protein Pre-formed fibrils (Cat. No. SPR-329)

  • and from a truncated form of human tau (K18) containing only the 4 microtubule binding repeats with a P301L (PL) mutation that promotes beta-sheet formation and the formation of PHFs.[4]
Active Human Recombinant Tau (K18), P301L mutant Protein Monomer (Cat. No. SPR-328)
Active Human Recombinant Tau (K18), P301L mutant Protein Pre-formed fibrils (Cat. No. SPR-330)

N.B: Both P301S and P301L mutant transgenic mouse models are used in tau research.

These active preformed fibrils have been shown to seed aggregation by recruiting monomers to form larger fibrils as demonstrated in the thioflavin T assays below.


Although full-length PFFs (T441) may be more effective in seeding fibrillisation than its truncated form (K18), a combination of both can be highly toxic to neurons.[5]

Further reading
- First Commercially Available Active Human and Mouse ASYN Proteins from StressMarq
- Short Articles on Alzheimer’s Disease:
#1 Amyloid beta formation
#2 Amyloid beta accumulation, imbalance of the production and clearance of Abeta
#3 Microglia
#4 Tau Phosphorylation


References
[1] Roles of tau protein in health and disease Guo, T., Noble, W., & Hanger, D. P. (2017). Acta Neuropathologica, 133(5), 665-704.
[2] Propagation of Tau aggregates, Michel Goedert and Maria Grazia Spillantini,
Molecular Brain, 201710:18
[3] What is the evidence that tau pathology spreads through prion-like propagation? Mudher A et al, Acta Neuropathol Commun. 2017; 5: 99.
[4] alzforum.org/mutations/mutation-position-table/mapt-p301-mutations
[5] Ozcelic, S. et al. Mol Psychiatry. 2016, 21(12): 1790–1798.

Written by Magalie Dale
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