Biochemistry of Tau in Alzheimer’s disease and related neurological disorders

Abstract

Microtubule-associated Tau proteins belong to a family of factors that polymerize tubulin dimers and stabilize microtubules. Tau is strongly expressed in neurons, localized in the axon and is essential for neuronal plasticity and network. From the very beginning of Tau discovery, proteomics methods have been essential to the knowledge of Tau biochemistry and biology. In this review, we have summarized the main contributions of several proteomic methods in the understanding of Tau, including expression, post-translational modifications and structure, in both physiological and pathophysiological aspects. Finally, recent advances in proteomics technology are essential to develop further therapeutic targets and early predictive and discriminative diagnostic assays for Alzheimer's disease and related disorders.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…A number of excellent reviews on the biology and pathology of Tau have appeared over the past few years (Cassimeris and Spittle 2001;Garcia and Cleveland 2001;Terwel et al 2002;Dehmelt and Halpain 2005;Andreadis 2006;Ballatore et al 2007;Gotz et al 2007Gotz et al , 2010Schneider and Mandelkow 2008;Sergeant et al 2008;Aguzzi and Rajendran 2009;Spires-Jones et al 2009;Iqbal et al 2009;Wolfe 2009;Goedert et al 2010;Morris et al 2011;Salminen et al 2011). This brief review will cover a few salient aspects, with an emphasis on Tau structure and interactions.…”

“…Some sites are efficient in detaching Tau from MT, notably S262 in R1, phosphorylated by MARK and related kinases , or S214 in the proline-rich domain, phosphorylated by PKA (Brandt et al 1994;Illenberger et al 1998). By contrast, proline-directed sites (SP or TP motifs) are prominently phosphorylated by the proline-directed kinases mentioned above, and although single sites have only a small effect, a combination of them can also considerably weaken the interactions with microtubules (Hernandez and Avila 2007;Sergeant et al 2008;Stoothoff and Johnson 2005). For the disease process, the important implication is that Tau is protected against aggregation while bound to MT, but not when it is detached by phosphorylation.…”

Tau Monoclonal Antibody Generation Based on Humanized Yeast Models

“…The ADx201 epitope is just adjacent to the Thr 217 residue, a known phosphosite of Tau associated with AD that is targeted by different kinases (4). To test whether the phosphorylation of Thr 217 influences the binding of ADx201, we performed an ELISA using synthesized peptides, one of which contained the phosphorylated Thr 217 ( Table 1).…”

“…During Alzheimer disease (AD), 5 a large pool of protein Tau becomes abnormally hyperphosphor-ylated, resulting in the loss of microtubule (MT) stabilization and the induction of conformational changes that allow the protein to oligomerize and aggregate into paired helical filaments (PHF) and neurofibrillary tangles (NFT) (4). The close correlation between the Tau pathology and the disease progression makes protein Tau a good biomarker for diagnosis.…”

The Microtubule-Dissociating Tau in Neurological Disorders

“…This typical tau profile was first characterized in AD, but now includes nine additional neurological disorders AD as cerebral aging (over 75 years), ALS/parkinsonismdementia complex of Guam, Parkinson with dementia of Guadeloupe, Niemann-Pick disease type C, Postencephalitic parkinsonism, Familial British dementia, Dementia pugilisticia, Down's syndrome and FTDP-17. Using histochemistry, aggregates of this class can be observed with AD2 and antibodies against exon 2 and exon 10 ( Buee L et al, 2000 andSergeant N et al, 2008). Fig.…”