Structure-based classification of tauopathies.

The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold.

Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.

Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies.

Tau Protein and Frontotemporal Dementias.

Filamentous inclusions of tau protein are found in cases of inherited and sporadic frontotemporal dementias (FTDs). Mutations in MAPT, the tau gene, cause approximately 5% of cases of FTD. They proved that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia.

Cryo-EM structures of tau filaments.

Assembly of microtubule-associated protein tau into filamentous inclusions underlies many human neurodegenerative diseases, called tauopathies. Tau inclusions display distinct cellular and neuroanatomical distributions in different tauopathies. Morphological and biochemical differences suggest that tau filaments adopt disease-specific molecular conformers, similar to prion strains.

Novel tau filament fold in corticobasal degeneration.

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls, and genome-wide association studies have identified additional risk factors. By histology, astrocytic plaques are diagnostic of CBD; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau.

Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse. No disease-modifying therapies currently exist, and diagnosis requires an autopsy.

Distinct Conformers of Assembled Tau in Alzheimer's and Pick's Diseases.

Tau filaments with distinct morphologies and/or isoform compositions underlie a large number of human neurodegenerative diseases. In conjunction with experimental studies, this has led to the suggestion that conformers of aggregated tau exist. Electron cryo-microscopy can be used to determine high-resolution structures of amyloid filaments from human brain.

Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer's and Pick's diseases.

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer's and Pick's diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin.

Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold.

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy).

Structures of filaments from Pick's disease reveal a novel tau protein fold.

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies seem to spread through specific neural networks in each disease, with short filaments having the greatest seeding activity. The abundance of tau inclusions strongly correlates with disease symptoms.

Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading.

The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. These diseases share common features with prion diseases, in which misfolded proteins can self-replicate and transmit disease across different hosts. Deciphering the molecular mechanisms that underlie the amplification of aggregates is fundamental for understanding how pathological deposits can spread through the brain and drive disease.

Galectin-8-mediated selective autophagy protects against seeded tau aggregation.

Assembled tau can transfer between cells and seed the aggregation of soluble tau. This process is thought to underlie the amplification and propagation of tau inclusions throughout the brain in neurodegenerative diseases, including Alzheimer's disease. An understanding of the mechanisms involved may provide strategies for limiting assembled tau propagation.

Cryo-EM structures of tau filaments from Alzheimer's disease.

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases.

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation.

Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived.

Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration.

The abnormal aggregation of a small number of known proteins underlies the most common human neurodegenerative diseases. In tauopathies and synucleinopathies, the normally soluble intracellular proteins tau and α-synuclein become insoluble and filamentous. In recent years, non-cell autonomous mechanisms of aggregate formation have come to the fore, suggesting that nucleation-dependent aggregation may occur in a localized fashion in human tauopathies and synucleinopathies, followed by seed-dependent propagation.

Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau.

The interneuronal propagation of aggregated tau is believed to play an important role in the pathogenesis of human tauopathies. It requires the uptake of seed-competent tau into cells, seeding of soluble tau in recipient neurons and release of seeded tau into the extracellular space to complete the cycle. At present, it is not known which tau species are seed-competent.

Conformation determines the seeding potencies of native and recombinant Tau aggregates.

Intracellular Tau inclusions are a pathological hallmark of several neurodegenerative diseases, collectively known as the tauopathies. They include Alzheimer disease, tangle-only dementia, Pick disease, argyrophilic grain disease, chronic traumatic encephalopathy, progressive supranuclear palsy, and corticobasal degeneration. Tau pathology appears to spread through intercellular propagation, requiring the formation of assembled "prion-like" species.