Tau oligomers and aggregation in Alzheimer’s disease

Abstract

J. Neurochem. (2010) 112, 1353–1367. Abstract We are analyzing the physiological function of Tau protein and its abnormal pathological behavior when this protein is self‐assemble into pathological filaments. These aggregates of Tau protein are the main components in many diseases such as Alzheimer’s disease (AD). Recent studies suggest that Tau acquires complex oligomeric conformations which may be toxic. In this review, we emphasized the possible phenomena implicated in the formation of these oligomers. Studies with chemical inductors indicates that the microtubule‐binding domain is the most important region involved in Tau aggregation and showed the requirement of a pre‐arrange Tau in abnormal conformation to promote self‐assembly. Transgenic animal models and AD neuropathology studies showed that post‐translational modifications are also implicated in Tau aggregation and neural cell death during AD development. Therefore, we analyzed some events that could be present during Tau aggregation. Finally, we included a brief discussion of the possible relation between glucose metabolism dysfunction in AD, and data of Tau aggregation by using aggregation inhibitors. In conclusion, the process Tau aggregation deserves further investigations to design possible therapeutic targets to inhibit the toxicity of these aggregates and it is possible that could be extended to other diseases with similar etiology.

Tau-Derived-Hexapeptide 306VQIVYK311 Aggregation Inhibitors: Nitrocatechol Moiety as A Pharmacophore In Drug Design

“…This further indicates that a nitrocatechol pharmacophore plays a major role in preventing AcPHF6 aggregation. Furthermore, a tolcapone derivative, methylbenzophenone (13), that lacks the critical nitrocatechol moiety failed to prevent AcPHF6 aggregation validating the critical nature of a nitrocatechol pharmacophore in preventing tau-hexapeptide aggregation ( Figure S5, Supporting Information).…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Most recent evidence suggests that oligomers and probably also protofibrils are toxic to neurons by disrupting synaptic function, membrane permeability, calcium homeostasis, gene transcription, mitochondrial activity, autophagy, and/or endosomal transport [18][19][20][21]. Moreover, recent studies have shown that propagation and seeding of Aβ, tau, and α-syn in a prion-like manner might also contribute to neurodegeneration [22][23][24][25][26][27][28].…”

Tau Oligomers as Potential Drug Target for Alzheimer Disease (AD) Treatment

“…Other stereological studies show that neuronal loss actually exceeds NFT formation (Gomez-Isla et al 1997, Terry 2000, van de Nes et al 2008, Vogt et al 1998. This and the exciting data published in the last half decade, emerging from biochemical, cell-based and transgenic mouse studies suggest that pre-filament forms of tau may be the most toxic and pathologically significant form of tau aggregates (Brunden et al 2008, Marx 2007, Meraz-Rios et al 2009). This evolutionary transition was overdue in the tau field and similar to the transition witnessed for A in the last 15 years driven by the characterization of A intermediate species and their crucial role in A -mediated toxicity (Harper et al 1997, Roher et al 1993, Walsh & Selkoe 2004, Walsh & Selkoe 2007.…”