Introduction:
We all are familiar with Alzheimer’s disease (AD), a progressive neurodegenerative disorder which is associated with deposition of ß-amyloid protein in the form of extracellular senile plaques and formation of neurofibrillary tangles made up of Tau protein. These abnormal proteins cause neuronal damage followed by neuron loss. Ever intrigued to know how these Tau proteins lead to the formation of neurofibrillary tangles? Let’s have a look what chemists has to say on this.
A recent study conducted by Aurelio J. Dregni and team at the Massachusetts Institute of Technology, United States reveals the chemistry behind this. In their research article titled ‘Fluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles’, they shed a light on the formation of intracellular neurofibrillary tangles by the microtubule-associated protein Tau and extracellular plaques formed by the β-amyloid peptide.
Isotopically labeled recombinant tau seeded with AD tau filaments conserves the AD pathogenic activity in wild-type neurons.
Research:
Tau protein exists in six isoforms on the basis of presence or absence of the second microtubule-binding repeat, R2. Tau isoforms containing four microtubule-binding repeats (R1, R2, R3, and R4) are called four-repeat (4R) tau, and those containing three microtubule-binding repeats (R1, R3, and R4) are called three-repeat (3R) tau.
The solid state nuclear magnetic resonance (NMR) spectroscopy was used to investigate AD-tau seeded 15N-labeled and 13C-labeled recombinant tau monomers with 10% AD brain-derived sarkosyl-insoluble tau. Brains of multiple AD patients were used to ensure that the molecular structural results observed reflect the average properties of AD brain tau filaments and not only of one patient. Eventually, the molecular level mixing of 4R and 3R tau isoforms in the neurofibrillary tangles was determined. It was observed that both the tau isoforms were fluently mixed in AD tau filaments in 60:40 incorporation ratio of 4R to 3R tau and a small homotypic preference. No detectable structural differences in the rigid β-sheet core or the mobile domains of pure 4R tau fibrils, pure 3R tau fibrils, and mixed 4R and 3R tau fibrils were seen. Thus, the ultrastructural morphology and pathological activities of Tau in AD are propagated by recombinant tau, irrespective of the presence of 4R tau, 3R tau or both the isoforms.
Conclusion:
The researchers have successfully revealed how two different forms of the Tau protein mix to form the neurofibrillary tangles in the brain by using NMR spectroscopy. The fluent molecular mixing of both 4R and 3R tau isoforms and the preservation of the β-sheet conformation regardless of the isoform was observed. This could be considered as the adaptive trait to optimize growth and propagation of the prion.
Reference:
Aurelio J. Dregni et al, Fluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles, Nature Communications (2022).
By Aditi Singh
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