Proteins enriched in amyloid plaques

Using LC-MS/MS, Liao et al. (2004) identified 26 brain proteins enriched in amyloid plaques excised with laser capture microdissection from AD brains. 

The proteins include cytoskeletal proteins (coronin, tau), membrane trafficking proteins (clathrin, dynamin 1, dynein), proteases (ATPases, cathepsin), 14-3-3 proteins, chaperons, and others. 

The proteomic analysis of the brain has certain limitations that are related either to the sample and/or analytical approach. In the analysis of the brain, many factors may be involved, such as differences among individuals, differences in age and sex, possible other diseases, treatment with medicines, as well as technical factors, disease-unrelated factors, such as postmortem time, improper treatment of the samples, etc., all of which can affect a clear discrimination between healthy and diseased states of interest. The technical limitations involve inefficient detection of low-abundance gene products, hydrophobic proteins (they do not enter the IPG strips), and acidic, basic, high-, and low-molecular mass proteins. All these protein classes are underrepresented in 2-D gels (Lubec et al., 2003 Fountoulakis, 2004). A combination of proteomics methods with protein separation, enriching techniques, and alternative methodologies for detection will improve the detection of additional differences between AD and control brains. Such differences may be essential in the discovery of early disease markers and therapeutic approaches. 

Agashe.V. R., Haetl, F. U. (2000). Roles of molecular chaperones in cytoplasmic protein folding. Semin. Cell Dev. Biol. 11, 15-25. 

Butterfield, D. A., Maekesbeey, W. R. (2000). Oxidative modification of creatine kinase BB in Alzheimer s disease brain. J. Neurochem. 74, 2520-2527. 

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Most proteomics analyses involve 2-D electrophoresis and MALDl-TOF MS steps, as this approach allows for a reliable quantification of changes in protein levels. In one study, the LC-MS/MS approach was used for the detection of proteins enriched in amyloid plaques in the AD brain (liao et al., 2004). Employing the former proteomic approach, levels of about 100 proteins were foimd to be changed in the AD brain and cerebrospinal fluid (CSF) in comparison with the control brain and CSF, respectively (Table 15.1). These proteins have various functions, mainly involved in neurotransmission, guidance, signal transduction, metabolism, detoxification, and conformational changes. The CSF proteins are plasma proteins. 

Coronin, achn binding protein Enriched in amyloid plaques Liao et al. 2004... 

Alzheimer s disease (AD) is one of the most common forms of dementia that affect the elderly population. The histopathological hallmarks of AD are extracellular deposits known as neuritic amyloid plaques and intraneuronal inclusions composed of hyperphosphorylated tangles enriched with tau proteins.1 The principal component of the neuritic plaques is aggregation of amyloid (A0), which is likely to play a role in the neurodegenerative process. The relative contribution of the various forms (soluble dimers, small oligomers, protofibrils, and fibrils) of A0 to neuronal... 

The mechanism of AD pathogenesis still remains unclear. However, one mechanism, amyloid (3 (A(3) accumulation, may be due to the disturbance in metal homeostasis in AD brains [Strausak et al., 2001]. A(3 peptides are the major constituents of the amyloid core of senile plaques, which are derived from the amyloid precursor protein (APP) and are secreted into extracelluar spaces. Both APP and A(3 contain a copper-binding domain [Hesse et al., 1994 Atwood et al., 1998]. High concentrations of copper, zinc, and iron have been found within the amyloid deposits in AD brains [Lovell et al., 1998], A(3 peptides can be rapidly precipitated by copper under mildly acidic conditions and by zinc at low physiological (submicromolar) concentrations [Bush et al., 1994], An age-dependent binding between A(3 peptides with excess brain metals (copper, iron, and zinc) induces A(3 peptides to precipitate into metal-enriched plaques [Bush, 2002],... 

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