Ultrastructural characteristics of tau filaments in tauopathies: Immuno‐electron microscopic demonstration of tau filaments in tauopathies

Abstract

The microtubule-associated protein tau aggregates into filaments in the form of neurofibrillary tangles, neuropil threads and argyrophilic grains in neurons, in the form of variable astrocytic tangles in astrocytes and in the form of coiled bodies and argyrophilic threads in oligodendrocytes. These tau filaments may be classified into two types, straight filaments or tubules with 9-18 nm diameters and "twisted ribbons" composed of two parallel aligned components. In the same disease, the fine structure of tau filaments in glial cells roughly resembles that in neurons. In sporadic tauopathies, individual tau filaments show characteristic sizes, shapes and arrangements, and therefore contribute to neuropathologic differential diagnosis. In frontotemporal dementias caused by tau gene mutations, variable filamentous profiles were observed in association with mutation sites and insoluble tau isoforms, including straight filaments or tubules, paired helical filament-like filaments, and twisted ribbons. Pre-embedding immunoelectron microscopic studies were carried out using anti-3-repeat tau and anti-4-repeat tau specific antibodies, RD3 and RD4. Straight tubules in neuronal and astrocytic Pick bodies were immunolabeled by the anti-3-repeat tau antibody. The anti-4-repeat tau antibody recognized abnormal tubules comprising neurofibrillary tangles, coiled bodies and argyrophilic threads in progressive supranuclear palsy (PSP) and corticobasal degeneration. In the pre-embedding immunoelectron microscopic study using the phosphorylated tau AT8 antibody, tuft-shaped astrocytes of PSP were found to be composed of bundles of abnormal tubules in processes and perikarya of protoplasmic astrocytes. In this study, the 3-repeat tau or 4-repeat tau epitope was detected in situ at the ultrastructural level in abnormal tubules in representative pathological lesions in Pick's disease, PSP and corticobasal degeneration.

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…Tau pathology is predominant in oligodendrocytes in multisystem atrophy, and the various mutations of FTDP-17 differ by the proportion of neuronal or glial tau pathology. 35,36 In AD patients, the number of NFTs correlates strongly with the degree of cognitive decline and neurodegeneration, and tau is commonly used as a diagnostic marker of AD. 37 The identification of patients in early disease stages is important, in light of recent findings of a positive correlation between early treatment with disease-modifying drugs and a prolonged maintenance of cognitive function.…”

Development of Tau Aggregation Inhibitors for Alzheimer's Disease

“…[12,13] The most common tauopathy is Alzheimers disease, but tau deposits also occur in frontotemporal dementias , Picks disease, Parkinsons disease, progressive nuclear palsy, and other conditions. [14,15] In Alzheimers disease, the brain contains two types of aggregates: intracellular neurofibrillary tangles (tau protein) and extracellular senile or "amyloid" plaques consisting of the Ab peptide, a cleavage product of the membrane protein APP. [16] Both types of aggregates are toxic for neurons, and both are based on the principle of amyloid aggregation, in which fibers are formed from the subunit protein by axial stacking of b strands, generating a cross-b-sheet structure at the core of the filaments.…”

Beta Amyloid Deposition and Neurofibrillary Tangles Spontaneously Occur in the Brains of Captive Cheetahs (Acinonyx jubatus)

“…34 The ultrastructural findings were consistent with so-called straight filaments, which comprise the NFTs in some types of tauopathies in humans. 2 However, it was different from the typical ultrastrucure of NFTs seen in AD (paired helical filaments).…”