Tau, prions and Aβ: the triad of neurodegeneration

Abstract

This article highlights the features that connect prion diseases with other cerebral amyloidoses and how these relate to neurodegeneration, with focus on tau phosphorylation. It also discusses similarities between prion disease and Alzheimer’s disease: mechanisms of amyloid formation, neurotoxicity, pathways involved in triggering tau phosphorylation, links to cell cycle pathways and neuronal apoptosis. We review previous evidence of prion diseases triggering hyperphosphorylation of tau, and complement these findings with cases from our collection of genetic, sporadic and transmitted forms of prion diseases. This includes the novel finding that tau phosphorylation consistently occurs in sporadic CJD, in the absence of amyloid plaques.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-010-0691-0) contains supplementary material, which is available to authorized users.

Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders

“…Also, according to this hypothesis, some of the members of this group of putative innate immunity proteins interact with each other during both their normal protective immune functions and during neurodegeneration. For example, the dPICs and some of the other IICs can become targets, or they can signal an innate immune response by other members of this group of innate immunity proteins (57,99). This unifying hypothesis explains the numerous findings suggesting various direct and indirect interactions among the members of this group of proteins.…”

Diversity of prion diseases: (no) strains attached?

“…mutant) alleles in determining glycotype, histological phenotype and clinical presentation. The second contribution is specifically dedicated to the E200K mutation [13]: It complements the previous article by providing an in-depth analysis of a the phenotypic variability of the E200K mutations and sheds light on the contribution of the codon 129 genotype to the phenotype: The article also reports a co-occurrence of considerable tau (as well as Ab and a-synuclein) pathology in many E200K patients and a comparison to the article by Reiniger et al [16] is highly recommended. A report of a family with detailed characterisation of two cases of seven OPRI (168 bp insertion) is also included in this cluster [10].…”

“…The review article by Reiniger et al [16] is a comprehensive and balanced synopsis of the amyloid cascade hypothesis and its relevance to prion disease, and it contains novel original data showing that tau hyperphosphorylation is a consistent feature of all sporadic, acquired and inherited forms of prion diseases, not only of those with formation of plaques, as was reported previously. The article also highlights the fact that PrP deposition and tau phosphorylation are strikingly congruent, and that the pattern of hyperphosphorylated tau deposits is distinct from that in Alzheimer's disease.…”

“…The common neuropathological features of prion diseases are a predominantly extracellular accumulation of PrP Sc in the central nervous system. Prion protein deposits can vary considerably in their pattern, distribution and intensity [16,18].…”

“Hot Spots” in Medicinal Chemistry

“…Tau is another neuronal protein that has received much attention more recently. [59] In AD and most other tauopathies, hyperphosphorylated tau dissociates from microtubules and accumulates into so-called paired helical filaments, which aggregate into pathological neurofibrillary tangles. Also here, misfolded tau appears to encourage normally folded tau to misfold and aggregate.…”