{"id":92,"date":"2019-10-14T02:34:19","date_gmt":"2019-10-14T06:34:19","guid":{"rendered":"http:\/\/www.creativebiomart.org\/alzheimacy\/?page_id=92"},"modified":"2021-12-09T22:06:57","modified_gmt":"2021-12-10T02:06:57","slug":"%ce%b3-secretase","status":"publish","type":"page","link":"https:\/\/www.creativebiomart.net\/alzheimacy\/target\/abeta-amyloid-pathway-as-drug-targets\/modulation-of-amyloid-beta-production\/r-secretase\/","title":{"rendered":"\u03b3-secretase"},"content":{"rendered":"

\u03b3-secretase (Gamma-secretase, GS) is involved in the\u00a0cleavage of the amyloid precursor protein (APP) in the amyloidogenic pathway. Specifically, \u03b2-secretase<\/a>\u00a0cleaves near the N-terminus of the A\u03b2 domain of APP to generate secreted APP\u03b2 (sAPP\u03b2) and a membrane-bound C-terminal fragment (C99) containing the entire A\u03b2 domain, which is further cleaved by \u03b3-secretase in a series of steps to generate A\u03b2 peptides of different lengths, of which A\u03b240 and A\u03b242 are the main products. The efficiency of the successive \u03b3-cleavage\u00a0affects the production ratio of toxic A\u03b242\u00a0to total A\u03b2.<\/p>\n

\u03b3-secretase is a multi-subunit enzyme complex with proteolytic activity, consisting of four different membrane proteins, namely, presenilin (PS1), presenilin enhancer 2 (PEN-2), nicastrin (NCT) and anterior pharynx-defective 1 (APH-1). PS1 is the catalytic subunit of \u03b3-secretase. \u03b3-secretase can cleave multiple type I\u00a0transmembrane proteins (over 90 reported substrates), of which APP and Notch are the best-characterized substrates.<\/p>\n


\nFigure 1. Atomic structure of \u03b3-secretase and its involvement in proteolytic processing of APP and Notch.\u00a0(Adapted from Bai X.; et al<\/em>.\u00a0An atomic structure of human \u03b3-secretase. Nature<\/em>. 2015.\u00a0525: 212-217; Gertsik N.; et al<\/em>.\u00a0Complex regulation of gamma-secretase: from obligatory to modulatory subunits. Frontiers in Aging Neuroscience<\/em>. 2015, 6: 342.)<\/p>\n

Current Situation and Challenges of \u03b3-secretase as the Target of AD <\/strong><\/p>\n

It is difficult to modulate A\u03b2 production by regulating \u03b3-secretase, in part because of the complexity of the \u03b3-secretase complex. The regulation of \u03b3-secretase complex activity is still far from being well understood. The four subunits that make up the complex and \u03b3-secretase-associated proteins are potential therapeutic targets.<\/p>\n

It is now known that \u03b3-secretase complex cleaves many different type I transmembrane protein substrates besides APP. In particular, \u03b3-secretase plays a crucial role in controlling the proteolysis of the transmembrane domain of the Notch receptors.\u00a0Inhibition of \u03b3-secretase by a \u03b3-secretase inhibitor (GSI) affects Notch signaling and can lead to severe adverse reactions. Therefore, the identification of highly selective and specific inhibitors poses a great drug-development challenge.<\/p>\n

Development Strategy and Focus <\/strong><\/p>\n

Regarding the development of Alzheimer's therapeutics targeting \u03b3-secretase, Alzheimacy hopes to help you in the development of a new generation of GSIs and \u03b3-secretase modulators (GSMs)<\/a>\u00a0that can selectively inhibit APP cleavage by \u03b3-secretase or\u00a0block the APP binding site rather than the active site of \u03b3-secretase.<\/p>\n

Alzheimacy is concerned with relatively safer disease-modifying therapies. For example, GSM that can modulate the activity of \u03b3-secretase, reduce the production of toxic A\u03b242 by shifting the APP cleavage toward the production of shorter and less aggregating A\u03b2 peptides, without affecting cleavage of Notch or other \u03b3-secretase substrates.\u00a0We also focus on novel targets, for instance, regulating the \u03b3-secretase complex by targeting \u03b3-secretase-associated proteins. Moreover, we support further develop basic research<\/a>\u00a0on \u03b3-secretase biology to advance the design of specific GSIs and GSMs. If you are interested in this and looking forward to technical support, please feel free to contact us<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"

\u03b3-secretase (Gamma-secretase, GS) is involved in the\u00a0cleavage of the amyloid precursor protein (APP) in the amyloidogenic pathway. Specifically, \u03b2-secretase\u00a0cleaves near the N-terminus of the A\u03b2 domain of APP to generate secreted APP\u03b2 (sAPP\u03b2) and a membrane-bound C-terminal fragment (C99) containing the entire A\u03b2 domain, which is further cleaved by \u03b3-secretase in a series of steps […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":87,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/pages\/92"}],"collection":[{"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/comments?post=92"}],"version-history":[{"count":5,"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/pages\/92\/revisions"}],"predecessor-version":[{"id":197,"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/pages\/92\/revisions\/197"}],"up":[{"embeddable":true,"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/pages\/87"}],"wp:attachment":[{"href":"https:\/\/www.creativebiomart.net\/alzheimacy\/wp-json\/wp\/v2\/media?parent=92"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}