{"id":87,"date":"2019-10-14T02:28:00","date_gmt":"2019-10-14T06:28:00","guid":{"rendered":"http:\/\/www.creativebiomart.org\/alzheimacy\/?page_id=87"},"modified":"2019-10-15T03:10:13","modified_gmt":"2019-10-15T07:10:13","slug":"modulation-of-amyloid-%ce%b2-production","status":"publish","type":"page","link":"https:\/\/www.creativebiomart.net\/alzheimacy\/target\/abeta-amyloid-pathway-as-drug-targets\/modulation-of-amyloid-beta-production\/","title":{"rendered":"Modulation of Amyloid \u03b2 Production"},"content":{"rendered":"

Background of Amyloid \u03b2 Production<\/strong><\/p>\n

Amyloid \u03b2 (A\u03b2) refers to a group of hydrophobic peptides composed of 39~43 amino acid residues, predominantly A\u03b240 and A\u03b242, whose pathological aggregation is thought to be implicated in\u00a0neuronal degeneration and cognitive decline in\u00a0Alzheimer\u2019s Disease\u00a0(AD). The A\u03b2 peptides are proteolytic fragments derived from amyloid precursor protein (APP), which is a\u00a0large\u00a0type I transmembrane protein, and there are three known pathways\u00a0to process APP.<\/p>\n\n\n\n\n\n\n
Pathway<\/strong><\/td>\nDescription<\/strong><\/td>\n<\/tr>\n
<\/td>\nThe non-amyloidogenic pathway is the primary pathway under physiological\u00a0conditions. APP is first cleaved by \u03b1-secretase, generating the soluble ectodomain sAPP\u03b1 and leaving the C-terminal fragment \u03b1 (CTF\u03b1) in the plasma membrane. CTF\u03b1 is subsequently cleaved by \u03b3-secretase to release the soluble extracellular p3 peptide and the APP intracellular domain (AICD).<\/td>\n<\/tr>\n
<\/td>\nThe first step of the amyloidogenic pathway is catalyzed by \u03b2-secretase, which cleaves APP to generate the soluble ectodomain sAPP\u03b2 and the CTF\u03b2\u00a0left in the membrane. Subsequently, the\u00a0CTF\u03b2 is\u00a0cleaved\u00a0by \u03b3-secretase\u00a0to produce A\u03b2 monomers and AICDs. Moreover, \u03b3-secretase cleaves the CTF\u03b2 at different sites and in multiple successive steps, producing various A\u03b2 species (including two major A\u03b2 peptides, namely A\u03b240 and A\u03b242).<\/td>\n<\/tr>\n
<\/td>\nA new APP processing pathway has recently been identified. This pathway yields proteolytic fragments derived from APP capable of inhibiting neuronal activity within the hippocampus. The cleavage of APP by \u03b7-secretase generates CTF\u03b7, which is cleaved by \u03b1-secretase and \u03b2-secretase into long and short amyloid \u03b7 (A\u03b7-\u03b1 and A\u03b7-\u03b2). There may be a connection between this pathway and the amyloidogenic pathway.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Strategies and Challenges in Modulating A\u03b2 Production<\/strong><\/p>\n

The amyloid cascade hypothesis<\/a>\u00a0suggests that the pathological aggregation of A\u03b2 is one of the main causes of AD. Thus, reducing A\u03b2 production has become an attractive R&D direction, particularly with a strong interest in \u03b2-secretase\u00a0and \u03b3-secretase as potential targets for drugs that might reduce A\u03b2 production.<\/p>\n