東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Sequential proteolysis by gamma-secr...

Fernandez, Marty Alyse.

FindBook

Google Book

Amazon

博客來

Sequential proteolysis by gamma-secretase and its implications for Alzheimer's disease.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Sequential proteolysis by gamma-secretase and its implications for Alzheimer's disease./
作者:	Fernandez, Marty Alyse.
面頁冊數:	178 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-04(E), Section: B.
Contained By:	Dissertation Abstracts International77-04B(E).
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3738762
ISBN:	9781339292410

Sequential proteolysis by gamma-secretase and its implications for Alzheimer's disease.
Fernandez, Marty Alyse.

Sequential proteolysis by gamma-secretase and its implications for Alzheimer's disease. - 178 p.

Source: Dissertation Abstracts International, Volume: 77-04(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2015.

The production and aggregation of the amyloid beta-peptide (Abeta) is thought to play a central role in Alzheimer's disease (AD) pathogenesis. The presenilin (PS)-containing gamma-secretase complex cleaves the amyloid beta-protein precursor C-terminal fragment (APP CTFbeta) to generate Abetas of 38-49 residues. Evidence suggests that these Abetas are the result of successive gamma-secretase cleavages, which are thought to start at the beta sites to generate Abeta48 or Abeta49, followed by C-terminal trimming mostly every three residues to produce secreted Abetas. Specifically, two product lines have been proposed: the Abeta49-46-43-40 line and the Abeta48-45-42-38 line. An increased proportion of aggregation-prone Abeta42 compared to Abeta40 is believed to be important in AD pathogenesis. Despite the apparent relevance of the production of the Abeta C-terminus in AD, questions surround the mechanisms by which gamma-secretase generates the Abeta spectrum and how familial AD-causing (FAD) mutations alter Abeta production.

ISBN: 9781339292410Subjects--Topical Terms:

518028
Biochemistry.

Sequential proteolysis by gamma-secretase and its implications for Alzheimer's disease.
LDR:03479nmm a2200313 4500 001 2077650
005 20161114130338.5
008 170521s2015 ||||||||||||||||| ||eng d
020 $a 9781339292410
035 $a (MiAaPQ)AAI3738762
035 $a AAI3738762
040 $a MiAaPQ $c MiAaPQ
100 1 $a Fernandez, Marty Alyse. $3 3193174
245 1 0 $a Sequential proteolysis by gamma-secretase and its implications for Alzheimer's disease.
300 $a 178 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-04(E), Section: B.
500 $a Adviser: Michael S. Wolfe.
502 $a Thesis (Ph.D.)--Harvard University, 2015.
520 $a The production and aggregation of the amyloid beta-peptide (Abeta) is thought to play a central role in Alzheimer's disease (AD) pathogenesis. The presenilin (PS)-containing gamma-secretase complex cleaves the amyloid beta-protein precursor C-terminal fragment (APP CTFbeta) to generate Abetas of 38-49 residues. Evidence suggests that these Abetas are the result of successive gamma-secretase cleavages, which are thought to start at the beta sites to generate Abeta48 or Abeta49, followed by C-terminal trimming mostly every three residues to produce secreted Abetas. Specifically, two product lines have been proposed: the Abeta49-46-43-40 line and the Abeta48-45-42-38 line. An increased proportion of aggregation-prone Abeta42 compared to Abeta40 is believed to be important in AD pathogenesis. Despite the apparent relevance of the production of the Abeta C-terminus in AD, questions surround the mechanisms by which gamma-secretase generates the Abeta spectrum and how familial AD-causing (FAD) mutations alter Abeta production.
520 $a This dissertation first examined the C-terminal trimming function of gamma-secretase and how PS FAD mutations alter this activity. We found that synthetic Abeta49, Abeta48, Abeta46, and Abeta45 are trimmed to Abeta40 and Abeta42 by gamma-secretase in vitro. Moreover, our results were consistent with the two-pathway model in which Abeta49 is primarily converted to Abeta40 and Abeta48 to Abeta42, but also demonstrated a small degree of crossover between the pathways. Most importantly, we found that PS1 FAD mutations dramatically reduce the efficiency of trimming of beta-cleaved Abetas, particularly the trimming of Abeta49 to Abeta40.
520 $a We also investigated substrate determinants for epsilon site endoproteolysis and C-terminal trimming of APP CTFbeta by gamma-secretase. The deletion of residues around the epsilon sites indicated that upstream sequences, and not depth within the transmembrane domain, are the determinants of epsilon site specificity. We also show that instability of the APP CTFbeta transmembrane helix near the epsilon site increases endoproteolysis, and that instability near the carboxypeptidase cleavage sites facilitates C-terminal trimming by gamma-secretase.
520 $a Last, the potential role of Abeta45-49 in AD pathogenesis was considered. We did not detect these Abeta species in AD brains by immunoprecipitation and western blot. However, we developed cellular systems to investigate their toxicity and obtained preliminary data suggesting that these Abetas may be neurotoxic.
590 $a School code: 0084.
650 4 $a Biochemistry. $3 518028
650 4 $a Cellular biology. $3 3172791
690 $a 0487
690 $a 0379
710 2 $a Harvard University. $b Medical Sciences. $3 3181716
773 0 $t Dissertation Abstracts International $g 77-04B(E).
790 $a 0084
791 $a Ph.D.
792 $a 2015
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3738762