17-20 Tau and neurofibrillary tangles Tau protein is a microtubule-associated
protein located In the neuronal axons. Due to alternative splicing of tau mRNA, there are 6 isoforms ranging in size from 352 to 441 andno acids, with molecular weights ranging from 50 to 65 kDa (Figure 2).21-24 Tau binds to tubulin In the axonal micro-tubules, thereby promoting Inhibitors,research,lifescience,medical microtubule assembly and stabillty21 Tau protein has more than 30 phosphorylation sites,21 either threonine or serine (Figure 2b), In AD, an abnormally hyperphosphorylated form of tau Is the principal component of the paired helical filaments (PHFs), which make up the neurofibrillary tangles, neuropil threads, and senile plaque neuritis.25 Due to the hyperphosphorylatlon, tau loses Its ability to bind to the microtubules and to stimulate their assembly, and also gets a tendency to aggregate.26 Inhibitors,research,lifescience,medical Figure 2. A. Schematic drawing of the six isoforms of tau protein. Alternatively spliced exons are marked. At the top, the smallest tau isoforms containing 352 andno acids, with three
repeat (microtubule-binding) domains. Below the other two three-repeat tau isoforms … Aβ and tau in CSF as biomarkers for AD The biochemical changes In the brain are reflected In CSF, and so CSF is an obvious source In the search for biomarkers for AD. There are two methods to search for CSF biomarkers: the Inhibitors,research,lifescience,medical candidate biomarker approach and the proteomlc approach. The candidate biomarker approach is based on the neurochemlstry of the central pathogenic processes In AD. Candidate Inhibitors,research,lifescience,medical biomarkers relate to proteins reflecting the neuronal degeneration, the metabolism and aggregation of Aβ, as well as the hyperphosphorylatlon of tau protein. The proteomic approach Is based on the identification of biomarkers that can differentiate AD from controls and other brain disorders, regardless of whether they are directly linked to the primary steps in AD pathogenesis. Proteomic
methods Include two-dimensIonal electrophoresis, protein chips, or liquid chromatography combined with mass spectrometry.27 Using the Inhibitors,research,lifescience,medical candidate biomarker approach, the three CSF biomarkers, total tau protein (T-tau), Aβ42, and various phosphorylated tau protein (P-tau) epitopes have been exandned in numerous studies, and have been found to have high diagnostic potential. Aβ42 isoform The first studies on CSF total Aβ used ELISA (enzyme-linked Immunosorbent assay) methods that did not discriminate between different Aβ Isoforms. Although some Idoxuridine studies found a slight decrease in total CSF Aβ in AD,28-30 other studies found no change.31-33 These negative results provided the conceptual basis for the development of ELISA methods http://www.selleckchem.com/products/epacadostat-incb024360.html specific for Aβ42.31,34 A large number of studies have evaluated the diagnostic potential for the most commonly used method for Aβ42,34,35 finding a sensitivity >85% and a specificity of 90% for discriminating between AD and normal aging.