PHF-Core Tau as the Potential Initiating Event for Tau Pathology in Alzheimer’s Disease

Abstract

Worldwide, around 50 million people have dementia. Alzheimer’s disease (AD) is the most common type of dementia and one of the major causes of disability and dependency among the elderly worldwide. Clinically, AD is characterized by impaired memory accompanied by other deficiencies in the cognitive domain. Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) are histopathological lesions that define brains with AD. NFTs consist of abundant intracellular paired helical filaments (PHFs) whose main constituent is tau protein. Tau undergoes posttranslational changes including hyperphosphorylation and truncation, both of which favor conformational changes in the protein. The sequential pathological processing of tau is illustrated with the following specific markers: pT231, TG3, AT8, AT100, and Alz50. Two proteolysis sites for tau have been described—truncation at glutamate 391 and at aspartate 421—and which can be demonstrated by reactivity with the antibodies 423 and TauC-3, respectively. In this review, we describe the molecular changes in tau protein as pre-NFTs progress to extracellular NFTs and during which the formation of a minimal nucleus of the filament, as the PHF core, occurs. We also analyzed the PHF core as the initiator of PHFs and tau phosphorylation as a protective neuronal mechanism against the assembly of the PHF core.

An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

“…Neurodegenerative diseases offer a broad spectrum of neurological diseases. Most often they are caused by the accumulation of intraneuronal bundles of hyperphosphorylated tau protein, in the form of neurofibrillary tangles, neuritic plaques and dystrophic neurites [96], as well as extracellular aggregates of beta-amyloid plaques, all characterizing Alzheimer's disease (AD). However, the link between amyloid deposits and neurofibrillary tangles is not yet clear, despite at least three decades of research devoted to finding the trigger factors of these proteinopathies and to understanding the timeline of molecular and biochemical events leading to their pathology [97].…”

Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration

“…In AD, eNFTs are composed primarily of the protease-resistant PHF-core comprised of a 92-95 amino acid fragment culminating at Glu391 and recognized by the 423 antibody. Truncation at Asp421, generated by caspase-3, has been associated with the early molecular stages of neurodegeneration in AD [20]. Truncation at Asp421 and Glu391 favor the polymerization of tau protein into highly insoluble filaments.…”

“…It is the minimal paired helical filament core fragment (PHF-core) [30][31][32] with a truncation at Glu391 [33], and which is recognized by the antibody 423 [34]. Recent studies have suggested that the PHF-core is an early initiating event of AD pathology [20]. It has been shown that the C-terminal region of tau is very susceptible to proteolysis [29,35].…”

Structural Analysis and Conformational Dynamics of Short Helical Hyperphosphorylated Segments of Tau Protein (Sequence 254–290) in Alzheimer’s Disease: A Molecular Dynamics Simulation Study

“…In general, the results showed that the interactions of the P-Ser262 complex were very similar to the control, but they increased significantly with increasing the number of phosphorylated sites to three. Indeed, as NC and NHB increase in P-Ser262, 285, 289 complex, the possibility of stable dimers increases, which is the first step in PHF formation ( Luna-Viramontes et al, 2020 ).…”