{"id":99,"date":"2019-10-14T02:44:59","date_gmt":"2019-10-14T06:44:59","guid":{"rendered":"http:\/\/www.creativebiomart.org\/alzheimacy\/?page_id=99"},"modified":"2019-10-15T03:09:30","modified_gmt":"2019-10-15T07:09:30","slug":"inhibiting-amyloid-proteins-aggregation","status":"publish","type":"page","link":"https:\/\/www.creativebiomart.net\/alzheimacy\/target\/abeta-amyloid-pathway-as-drug-targets\/inhibiting-amyloid-proteins-aggregation\/","title":{"rendered":"Inhibiting Amyloid Proteins Aggregation"},"content":{"rendered":"

Background of Amyloid Proteins\u00a0Aggregation <\/strong><\/p>\n

The amyloid \u03b2 (A\u03b2) monomer that is present in neurons in the human brain performs important tasks for neurons. However, in the brains of patients with Alzheimer\u2019s Disease (AD), the A\u03b2 monomer (mainly 40 and 42 amino acid residues in length)\u00a0has\u00a0lost its normal physiological function and spontaneously self-assembles to form aggregates and then protofibrils, which are a heterogeneous class of soluble prefibrillar species with a characteristic secondary and super-secondary structure. The protofibrils continue to form fibrils, which can finally form large deposits called plaques. It is now widely\u00a0agreed that the soluble A\u03b2 oligomers, rather than amyloid plaques, constitute\u00a0the primary\u00a0cause of toxicity, and A\u03b242 seems to be the most toxic A\u03b2 isoform\u00a0owing to its high tendency to form fibrillary and non-fibrillary aggregates.<\/p>\n


\nFigure 1. Schematic diagram of A\u03b2 aggregation process from monomer to plaque. (Graham W V.; et al<\/em>. Update on Alzheimer\u2019s disease therapy and prevention strategies. Annual Review of Medicine<\/em>. 2017, 68(1): 413-430.)<\/p>\n

The A\u03b2 aggregation process is extremely complicated, and consists of at least four\u00a0microscopic chemical events:<\/p>\n\n\n\n\n\n\n\n
Microscopic Chemical Event <\/strong><\/td>\nDescription<\/strong><\/td>\n<\/tr>\n
Primary Nucleation of Monomers<\/td>\nMonomers interact with each other in solution to form initial small soluble aggregates.<\/td>\n<\/tr>\n
Elongation of Fibrils<\/td>\nExisting fibrils increase in length by the addition of monomers.<\/td>\n<\/tr>\n
Fibril Fragmentation<\/td>\nExisting fibrils break apart, increasing the total number of fibrils.<\/td>\n<\/tr>\n
Secondary Nucleation of Monomers on Fibril Surface<\/td>\nThe surface of existing aggregates catalyzes the formation of new small soluble aggregates.\u00a0It is considered that most toxic species are generated from the process.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The non-linearity of this process produces a heterogeneous population of amyloid protein species, which means that pathological A\u03b2\u00a0aggregation can be prevented by targeting specific molecular intermediates in the pathway from monomers to plaques or specifically targeting steps involved in toxicity.<\/p>\n

Strategies and Challenges in Inhibiting Amyloid Proteins\u00a0Aggregation <\/strong><\/p>\n

Various strategies have been utilized to interfere with the aggregation process by targeting diverse amyloid conformation species:<\/p>\n