Tauopathies: One Disease or Many?

Abstract

Tauopathies are a group of disorders that have in common abnormal accumulation of tau protein in the brain. Although the different tauopathies have long been considered to be separate diseases, it is now clear that progressive supranuclear palsy, corticobasal degeneration and some forms of tau-positive frontotemporal lobar degeneration share clinical, pathological and genetic features. The important overlap between these disorders suggest they may represent different phenotypes of a single disease process, the clinical result depending on the topography of pathological lesions as well as other unknown factors.

Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

“…Here, we questioned whether the ExoY ϩ -induced phosphorylated, insoluble tau accumulates outside the cell in a high-molecular-weight form, characteristic of such chronic neurodegenerative tauopathies as Alzheimer's disease (8,48). In our previous work utilizing the Tau-5 antibody to detect total tau and the phosphorylated (Ser 214 ) tau antibody to detect phosphorylated tau, we found no evidence of a highmolecular-weight endothelial tau.…”

“…ExoY generates a cyclic nucleotide signature that activates protein kinases A and G, resulting in hyperphosphorylation and insolubility of the endothelial tau (41). In neural disease, tau hyperphosphorylation and insolubility lead to its oligomerization, which is a hallmark of neurodegenerative tauopathies (8,48). However, in previous studies we were unable to detect ExoY-induced tau oligomerization in endothelial cell lysates, an effect that was attributed to phosphorylation at Ser 214 , because tau phosphorylation at this site has been shown to inhibit aggregation (57).…”

“…The reason for such long-lasting deleterious effects is unclear, although studies in dementia models may provide some insight. Hyperphosphorylated, insoluble tau oligomerizes within neurons (8,48) and can be released into the extracellular space (52). Nearby cells endocytose oligomerized tau, and the abnormal oligomer nucleates monomeric tau as a mechanism of disease propagation (19,28).…”

Pseudomonas aeruginosa Exotoxin Y Is a Promiscuous Cyclase That Increases Endothelial Tau Phosphorylation and Permeability

“…Finally, we demonstrate that accumulation of cytosolic cAMP, and not cGMP, leads to large interendothelial gaps and increased permeability in pulmonary microvascular endothelial cells. Because hyperphosphorylated and insoluble Tau are hallmarks of neurodegenerative tauopathies such as Alzheimer disease (30,31), these findings suggest that acute P. aeruginosa infections and chronic neurodegenerative diseases share Tau hyperphosphorylation and insolubility as a common pathophysiological mechanism.…”

Original article Hemimegalencephaly: foetal tauopathy with mTOR hyperactivation and neuronal lipidosis

“…The mono clonal antibody we used against the phosphorylated form of tau is not found in normal brain in adults or in immature brain during development. Whereas tauopathies in adults represent several different diseases, each with distinct clinical and neuropathological features, it is suggested that the overlap actually may be different phenotypes of a similar disease process [4]. Perhaps our foetal/infantile tauopathy here described is yet another part of this spectrum.…”