(DOWNLOAD) "Altered Production of Aβ by Mutations of the Amyloid Protein Precursor Linked to Familial Alzheimer’s Disease" by Xiao-Dan Cai ~ eBook PDF Kindle ePub Free
eBook details
- Title: Altered Production of Aβ by Mutations of the Amyloid Protein Precursor Linked to Familial Alzheimer’s Disease
- Author : Xiao-Dan Cai
- Release Date : January 19, 2013
- Genre: Medical,Books,Professional & Technical,
- Pages : * pages
- Size : 14806 KB
Description
Alzheimer's disease (AD) is a neurodegenerative disease characterized by neuronal loss, neurofibrillary tangles, and amyloid plaques. The principal component of the amyloid plaques is Aβ, a peptide of 39-43 amino acid residue, which is derived from an integral membrane protein, amyloid β protein precursor (βAPP). The discoveries of mutations in the βAPP gene that cosegregate with the AD phenotype (FAD) have provided strong evidence that amyloid deposition plays a critical role in the development of AD, though how these mutations cause AD remains to be answered. I have focused my study on the pathogenic mechanism of those mutations of βAPP gene linked to FAD. By showing that the βAPPΔNL mutation increases Aβ production six-fold, I provided strong evidence for the first time that this mutation caused AD because its processing was altered in a way that increased the production of Aβ, thereby promoting amyloid deposition. However, my initial study of βAPPΔIle showed that it did not increase the total amount of Aβ production. Based on published in vivo and in vitro data suggesting that the C-termini of Aβ are heterogeneous and that longer Aβ forms aggregate more rapidly, we hypothesized that the C-terminal mutations might promote amyloid deposition by favoring the genesis of longer Aβ. In collaboration with Toby Cheung, and later, Dr. Suzuki, we tested the hypothesis and provided evidence that βAPPΔIle and βAPPΔPhe increased the proportion of Aβ1-42 when compared to βAPP wild type. To study the mechanism by which βAPPΔNL promotes Aβ production, I further characterized the proteolytic processing of βAPPWT and βAPPΔNL both in full length and shortened constructs. My results indicate that βAPPΔNL promotes Aβ production by favoring the cleavage at the N- terminal of Aβ over the one within Aβ sequence. In order for cells to produce Aβ, a cleavage C-terminal to Aβ, a site located within the transmembrane domain of βAPP, must occur. Until now, no model of βAPP processing can explain how this can happen. Based on the principles of cell biology, I will try to integrate the process of autophagocytosis into βAPP processing, and to propose a hypothesis which emphasizes topological transposition and degradation of membrane as prerequisites for Aβ genesis. I will also discuss possible strategies to test the hypothesis.
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