The Role of Tau beyond Alzheimer's Disease: A Narrative Review

Abstract

Nowadays, there is a need for reliable fluid biomarkers to improve differential diagnosis, prognosis, and the prediction of treatment response, particularly in the management of neurogenerative diseases that display an extreme variability in clinical phenotypes. In recent years, Tau protein has been progressively recognized as a valuable neuronal biomarker in several neurological conditions, not only Alzheimer's disease (AD). Cerebrospinal fluid and serum Tau have been extensively investigated in several neurodegenerative disorders, from classically defined proteinopathy, e.g., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), but also in inflammatory conditions such as multiple sclerosis (MS), as a marker of axonal damage. In MS, total Tau (t-Tau) may represent, along with other proteins, a marker with diagnostic and prognostic value. In ALS, t-Tau and, mainly, the phosphorylated-Tau/t-Tau ratio alone or integrated with transactive DNA binding protein of ~43 kDa (TDP-43), may represent a tool for both diagnosis and differential diagnosis of other motoneuron diseases or tauopathies. Evidence indicated the crucial role of the Tau protein in the pathogenesis of PD and other parkinsonian disorders. This narrative review summarizes current knowledge regarding non-AD neurodegenerative diseases and the Tau protein.

Keywords: Parkinson’s disease; Tau; amyotrophic lateral sclerosis; biomarkers; frontotemporal spectrum disorder; multiple sclerosis; neurodegeneration; prognosis; tauopathies.

Figure 1

Tau protein in the central nervous system. (a) Tau protein is a microtubule associated protein (MAP) that contributes with others MAP to axonal stabilization in healthy neurons; (b) phosphorylation of Tau will reduce affinity for microtubule, and in many neurodegenerative diseases, hyperphosphorylated-Tau will induce neuronal death; (c) upon any axonal damage from aging or pathological damage such as inflammation, t-Tau, and p-Tau will be released in CSF. Lower concentrations can also be found in peripheral blood. Abbreviations: CSF: cerebrospinal fluid. Created with Biorender.com.

Figure 2

Overview of the role of Tau protein in different non-AD neurodegenerative disease. Abbreviations: ALS: amyotrophic lateral sclerosis, FTSD: frontotemporal spectrum disorder; MS: multiple sclerosis; PD: Parkinson’s disease. Figure created with Biorender.com.