Tau pathology and neurodegeneration

Summary

The pathway leading from soluble and monomeric to hyperphosphorylated, insoluble and filamentous tau protein is at the centre of many human neurodegenerative diseases, collectively referred to as tauopathies. Dominantly inherited mutations in MAPT, the gene that encodes tau, cause forms of frontotemporal dementia and parkinsonism, proving that dysfunction of tau is sufficient to cause neurodegeneration and dementia. However, most cases of tauopathy are not inherited in a dominant manner. The first tau aggregates form in a few nerve cells in discrete brain areas. These become self propagating and spread to distant brain regions in a prion-like manner. The prevention of tau aggregation and propagation is the focus of attempts to develop mechanism-based treatments for tauopathies.

Introduction

The progressive dysfunction and death of nerve cells characterise the most common neurodegenerative diseases in human beings, including Alzheimer's disease and Parkinson's disease. The clinical picture is defined by the affected brain regions, explaining why Alzheimer's disease is a dementing disease and Parkinson's disease mainly a movement disorder. No mechanism-based treatments for these diseases are available, and those treatments that exist are symptomatic.

Specific protein inclusions define most neurodegenerative diseases at the pathological level. In 1907, Alois Alzheimer in Munich, Germany, and Oskar Fischer in Prague, Czech Republic, described the association between dementia and the presence of abundant neuritic plaques and neurofibrillary tangles visualised with silver stain in the cerebral cortex.1, 2, 3, 4 3 years later, Emil Kraepelin, head of the Munich Institute, named a form of presenile dementia after Alzheimer and suggested that Alzheimer's disease was distinct from senile dementia, which has an onset of disease after 65 years of age.⁵ In 2013, the Phe176Leu mutation in PSEN1, the gene encoding presenilin 1, was identified in Alzheimer's first patient Auguste Deter, who had an age of disease onset of 51 years.⁶ In the 1970s, the general belief was that most patients with senile dementia had similar pathological changes in their brains to patients in their presenium with Alzheimer's disease. As a result, the idea of Alzheimer's disease was widened to include cases of senile dementia.⁷

In 1911, Alzheimer described argyrophilic inclusions in a form of frontotemporal dementia⁸ that was subsequently named Pick's disease, after Arnold Pick, head of the Department of Neuropsychiatry at the German University in Prague where Fischer worked. These inclusions are now known as Pick bodies. In 1912, Fritz Heinrich Lewy described the inclusions characteristic of Parkinson's disease (Lewy bodies and Lewy neurites) in Alzheimer's laboratory in Munich.9, 10 Electron microscopy showed that all these inclusions are made of abnormal filaments. In the past 30 years, a causal connection has been established between the formation of inclusions and the process of degeneration; the molecular components of the inclusions were identified and the causes of rare inherited forms of Alzheimer's disease, Parkinson's disease, and frontotemporal dementia were discovered. In most cases, pathogenic mutations caused disease through an overproduction of the amyloidogenic protein or an increase in the protein's propensity to aggregate. Similar toxic mechanisms might underlie the sporadic forms of disease.

Neurofibrillary tangles and Pick bodies made of the microtubule-associated protein tau in a hyperphosphorylated and filamentous state form inside some brain cells (figure 1).¹¹ In the 1980s and early 1990s, immunohistochemistry, electron microscopy, biochemistry, and molecular biology were used to establish that the paired helical and straight filaments seen in the brains of patients with Alzheimer's disease are made of all brain isoforms of the microtubule-associated protein tau in a hyperphosphorylated state.13, 14, 15, 16, 17, 18, 19, 20 In the late 1990s, mutations in MAPT, the gene encoding tau, were shown to cause an inherited form of frontotemporal dementia and parkinsonism, with high disease penetrance and characterised by abundant hyperphosphorylated filamentous tau inclusions, proving that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia.21, 22, 23 More recently, chronic traumatic encephalopathy, a neurodegenerative disease resulting from environmental causes including repetitive blast or concussive injuries, or both, was also found to be characterised by filamentous tau inclusions (figure 1).12, 24, 25 The disease was originally described as the clinical deterioration that occurs after repetitive brain trauma in boxers.²⁶

Alzheimer's disease is defined by the presence of two types of abnormal protein deposits: extraneuronal amyloid β and intraneuronal tau.13, 14, 15, 16, 17, 18, 19, 20, 27, 28 Intraneuronal tau inclusions are also characteristic of diseases associated with extracellular deposits made of integral membrane protein 2 (the Bri peptide)²⁹ and some cases of Gerstmann-Sträussler-Scheinker disease with extracellular deposits of the prion protein.³⁰ The conversion of soluble to insoluble filamentous tau protein is central to many human neurodegenerative diseases (panel); therefore, tau is an excellent potential therapeutic target.

We review evidence showing that tau assembly is essential for the pathogenesis of many human neurodegenerative diseases, collectively referred to as tauopathies, and discuss implications for the development of mechanism-based treatments.