Primary age-related tauopathy

Primary age-related tauopathy (PART) is a

Owing to these imaging and staining advancements, tau has been identified to be associated with microtubules in neuron cells.[20] Tau protein stabilize the microtubules and are involved in fast dendrite growth, retrograde and antegrade transport intracellularly and neuron maintenance.^[20]

Tau protein is divided into three segments, i.e. N-terminal (regulated spacing of microtubules), C-terminal (microtubule polymerization), proline rich domain (kinase) and microtubule binding domain.^[12] Tau in brain of patients with tauopathies is hyperphosphorylated which causes the tau protein to dissociate from the microtubule then aggregate in to β-plated sheet arrangement.^[12] PART cases is due to tau protein isoforms (3 and 4 microtubule binding repeats) abnormal ration inneural cells resulting in their self assembling and accumulation resulting in NFT formation in brain.^[12][17][18] Detachment of tau from microtubules causes the neuron to lose its ability to sustain its self and thus ultimately loses function.

Hyper-phosphorylation of tau protein was initially thought to be caused by Aβ₄₂ but since PART cases generally lack senile plaques, other causes were investigated. One such cause was found to me the microtubule affinity-regulating kinase (MARK) since it is involved in tau phosphorylation and dephosphorylation.

Recent finding's on tau regulation has revealed small non coding RNAs bind to recognition motifs on mRNAs and silence their expression through post-translational regulation.^[21] MiRNA-219 binds to tau mRNA and represses tau protein synthesis since in fly model brain, over expression of miRNA-219 reduced the tau protein accumulation.^[21]

Treatment

These options listed below have not been yet linked or specified for PART treatment since the disease is yet to gain acceptance as a unique abnormality case by the medical community. Thus the treatments represent possible future options as per the research and finding in the medical literature.

HSP90 Targets

PU-DZ8 can pass the blood brain barrier and act on HSP90 to inhibit it.^[18]

Small molecule inhibitors

Staurosporine, Methylene blue and other kinase inhibitors can pass the blood brain barrier and inhibit MARK which consequently down regulation tau protein hyper-phosphorylation and ultimately its detachment from microtubules.^[19]

References