Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

Lucke Wold B

doi:10.19104/jnn.2017.40

Abstract

Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.

Highlights

Tau hyperphosphorylation and progression have long dominated the underlying dogma behind disease progression in Alzheimer’s disease (AD) and Chronic Traumatic Encephalopathy (CTE)
Less staining was seen in the thalamus. Such early staining likely indicates the initial pathology in disease progression, which proceeds tau hyperphosphorylation
A strategy to slow tau acetylation seems plausible as a method to prevent disease onset and progression

Summary

Introduction

Tau hyperphosphorylation and progression have long dominated the underlying dogma behind disease progression in Alzheimer’s disease (AD) and Chronic Traumatic Encephalopathy (CTE). Our group and others have shown that looking earlier in the disease process may be more valuable in finding a treatment solution that can be clinically successful Secondary injury mechanisms such as oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation play a more important role in disease onset than previously assumed [1,2,3,4]. These secondary injury mechanisms can be primed by genetic predisposition and triggered by insults such as neurotrauma, drug abuse, and cardiovascular disease [5,6,7] Once activated, these cascades lead to persistent damage to neurons and surrounding glia causing distinct tau acetylation [8]. We highlight the relationship of tau acetylation to AD and CTE and discuss the most effective strategy for reducing tau acetylation via pharmaceutical intervention

Methods

Results

Conclusion