Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers

Abstract

The deposition of highly phosphorylated and aggregated tau is a characteristic of tauopathies, including Alzheimer's disease. It has long been known that different isoforms of tau are aggregated in different cell types and brain regions in each tauopathy. Recent advances in analytical techniques revealed the details of the biochemical and structural biological differences of tau specific to each tauopathy. In this review, we explain recent advances in the analysis of post‐translational modifications of tau, particularly phosphorylation, brought about by the development of mass‐spectrometry and Phos‐tag technology. We then discuss the structure of tau filaments in each tauopathy revealed by the advent of cryo‐EM. Finally, we describe the progress in biofluid and imaging biomarkers for tauopathy. This review summarizes current efforts to elucidate the characteristics of pathological tau and the landscape of the use of tau as a biomarker to diagnose and determine the pathological stage of tauopathy.

An open chat with… Koji Yamanaka

“…Sahara and Higuchi reviewed recent advances in tau biology, in vivo diagnostic imaging and the development of tau‐targeted therapies [ 1 ]. Kimura and Tomita provided a review focusing on the structural diversity of tauopathy and its implication in disease and biomarkers [ 2 ]. Kawade and Yamanaka reviewed brain lipid metabolism in AD and its implication in oligodendrocyte abnormalities, an under‐investigated aspect of AD [ 3 ].…”

Role of Amyloidogenic and Non‐Amyloidogenic Protein Spaces in Neurodegenerative Diseases and their Mitigation Using Theranostic Agents

“…It is characterized by accumulation of Aβ plaques resulting from abnormal APP processing and neurofibrillary tangles of tau protein [7,8] . Tau undergoes hyperphosphorylation, misfold and aggregates to form neurofibrillary tangles results in numerous NDDs, such as AD, Argyrophilic Grain Disease (AGD), Pick's disease (PiD), Chronic Traumatic Encephalopathy (CTE), Frontotemporal Degeneration (FTP), Corticobasal Degeneration (CBD), Progressive supranuclear palsy (PSP) and Primary Age‐Related Taupathy (PART) collectively called as tauopathies [9,10] . Each tauopathy has a unique set of clinical symptoms, distribution, course and structural similarities and differences in microstructures of tau fibrils shown by a Cryo‐Electron microscope [11–15] .…”

“…[7,8] Tau undergoes hyperphosphorylation, misfold and aggregates to form neurofibrillary tangles results in numerous NDDs, such as AD, Argyrophilic Grain Disease (AGD), Pick's disease (PiD), Chronic Traumatic Encephalopathy (CTE), Frontotemporal Degeneration (FTP), Corticobasal Degeneration (CBD), Progressive supranuclear palsy (PSP) and Primary Age-Related Taupathy (PART) collectively called as tauopathies. [9,10] Each tauopathy has a unique set of clinical symptoms, distribution, course and structural similarities and differences in microstructures of tau fibrils shown by a Cryo-Electron microscope. [11][12][13][14][15] 3R and 4R tau isoforms core structures are found both in sporadic and familial cases of AD whereas a distinct tau structure is reported in PiD involving unique fold from amino acids 254-378 of the 3R tau isoforms resulting it being different from that of AD.…”