Abstract
All tauopathies, including Alzheimer’s disease (AD), are characterized by the intracellular accumulation of abnormal forms of tau protein in neurons and glial cells, which negatively affect microtubule stability. Under physiological conditions, tubulin-associated unit (Tau) protein is intrinsically disordered, almost without secondary structure, and is not prone to aggregation. In AD, it assembles, and forms paired helical filaments (PHFs) that further build-up neurofibrillary tangles (NFTs). Aggregates are composed of hyperphosphorylated tau protein that is more prone to aggregation. The pathology of AD is also linked to disturbed copper homeostasis, which promotes oxidative stress (OS). Copper imbalance is widely observed in AD patients. Deregulated copper ions may initiate and exacerbate tau hyperphosphorylation and formation of β-sheet-rich tau fibrils that ultimately contribute to synaptic failure, neuronal death, and cognitive decline observed in AD patients. The present review summarizes factors affecting the process of tau aggregation, conformational changes of small peptide sequences in the microtubule-binding domain required for these motifs to act as seeding sites in aggregation, and the role of copper in OS induction, tau hyperphosphorylation and tau assembly. A better understanding of the various factors that affect tau aggregation under OS conditions may reveal new targets and novel pharmacological approaches for the therapy of AD.
Highlights
Tubulin-associated unit (Tau) is a microtubule-associated phosphoprotein predominantly expressed in neuronal cells, mainly in axons
Deregulation of copper homeostasis promotes an oxidative stress (OS) condition that is recognized as an early event in Alzheimer’s disease (AD)
Recent findings demonstrate the catalytic role of Cu2+ in aggregation as it triggers conformational changes of tau peptides located in the microtubule-binding domain
Summary
Tubulin-associated unit (Tau) is a microtubule-associated phosphoprotein predominantly expressed in neuronal cells, mainly in axons. It is essential for proper assembly, stabilization, and functioning of a microtubule network. Regarding tau-related pathology, the major difference between the isoforms is located in the microtubule-binding domain that contains three or four imperfect pseudorepeat units (R1–R4). The N-terminal part of tau determines the spacing between microtubules and does not participate in microtubule binding (Schneider et al, 1999; Kadavath et al, 2015; Cheng and Bai, 2018; Barbier et al, 2019). Tau remains highly dynamic despite being bound to microtubules These small groups of microtubule-binding motifs stabilize protofilament conformation of microtubules by binding to a hydrophobic pocket at the interface between α-β-tubulin heterodimers. The residues participating in binding to microtubules are critically involved in tau aggregation, a hallmark feature of AD (Kadavath et al, 2015)
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