The Molecular Basis of Alzheimer Disease

The Molecular Basis of Alzheimer Disease

Function of APP Gene

The biological function of the APP is of key interest when the research on Alzheimer is carried out. However the vague results are found which hinder the process of thorough understanding. Research suggests that the repair and synaptic formation are the major roles of APP gene (Zheng &Koo 2006, p. 5). It is also the function of APP gene to up-regulate during and after neuronal injury and differentiation. Many other functions of APP gene are still researched at limited levels but it is revealed that the cell adhesions, roles in cell signaling and long term potentiation are the other functions (Bauer et.al 2006, pp. 7214). Also the signaling role of the surface receptor protein is compared with the post translational processing similarities (Selkoe & Kopan 2003, pp. 577).

Formation and Accumulation of Amyloid Plaques

The APP sequence is found to be containing the largely independently-folding structural domains which are also distinct in nature. There are two regions which are intracellular and extracellular where the extracellular region is divided into two domains which are E1 and E2. The first domain is E1 in which there are many other subdomains. One such domain is the GFLD, growth factor like domain, which is a metal binding motif. Another domain is the serine protease inhibitor domain (Kong et.al 2005, p. 93). Another domain is E2 in which there is a dimerization motif that is coiled coil and it binds the proteoglycans in the extracellular matrix (Matsuyama et.al 2007, pp. 1085).

Figure: Processing of APP in the amyloidogenic pathway

Source: http://www.sciencedirect.com/science/article/pii/S0925443906002675

Till present the complete formation and accumulation of APP has not been uncovered but the individual domains that form APP are found to be crystallized successfully. These include the zinc binding as well as the copper binding domains along with the E2 dimerization domain. Thus multiple configurations exist in the ion binding states (Borg et.al 1996, pp. 6234).

The post translational modifications in the APP include many types of processing of proteolytic to the fragments that are generating peptide (Lefterov et.al 2000, pp. 1841). Other extension modifications are tyrosine sulfation, glycosylation and phosphorylation. The secretase that are commonly cleaved by the proteases are the alpha and beta from the secretase family. Both of these secretases are responsible for removing the entire extracellular domain. This releases the fragments that are membrane-anchored carboxy-terminal. These fragments are also associated with the apoptosis (Hashimoto 2002, pp. 1530). The gamma secretase cleavage lies within the domain of membrane spanning. It is responsible for generating the fragment of amyloid-beta. this secretase is found to be the major genetic risk factor that causes Alzheimer. The gamma secretase is a complex that is large and subunit at multiple levels (Crowther 2005, pp. 124). The components of this secretase have not been fully characterized but it is found that it contains presenilin (Ohsawa et.al 2001, pp. 1415).

Lipid rafts are also found to be linked with the amyloidogenic processing of APP. The beta secretase accesses and differentially cleaves ...