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

Nabil Itzi Luna-Viramontes,Ignacio Villanueva-Fierro,José Luna-Muñoz,Charles R Harrington,Fidel De La Cruz,Sandra Martínez-Robles,Linda Garcés-Ramírez,Erik González-Ballesteros,Mario Hernandes-Alejandro,Parménides Guadarrama-Ortíz,B Berenice Campa-Córdoba,Miguel Ángel Ontiveros-Torres,Mar Pacheco-Herrero

doi:10.3389/fncel.2020.00247

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.

Highlights

The elderly population is increasing globally, and this leads to the increased prevalence of neurodegenerative diseases typical of this age group
Tau phosphorylation and neurofibrillary tangles (NFTs) formation seem to act as a protective event against the minimal nucleus of the filament (PHF core), which functions as a prion and is highly toxic
Taking into account that NFTs are closely correlated with the cognitive deterioration of patients, it is vitally important to look for other proteins that can define the early onset of Alzheimer’s disease (AD)

Summary

INTRODUCTION

The elderly population is increasing globally, and this leads to the increased prevalence of neurodegenerative diseases typical of this age group. These filaments are exposed as extracellular NFTs, which is only detected using the TR dye and the antibody 423 (truncation in Glu-391) This stage is characterized by a loose fibrillar structure in which the cell membrane and the nucleus have been lost (Figure 1F; Mena et al, 1991; Galvan et al, 2001; Luna-Munoz et al, 2007). The toxicity of the truncated tau (92–95 amino acids) is associated with the high affinity of the intact tau and the phosphorylated tau to this small fragment (Figure 7, step 2), which would trigger an immediate neuroprotective mechanism This would be reflected by the hyperphosphorylation of the tau molecule in a failed attempt to hide the PHF core and avoid the kidnapping of the molecules of intact tau. Bring hope of discovering effective methods to both diagnose and cure AD

ETHICS STATEMENT

CONCLUSION