Gamma Secretase Signalling Pathway

Accumulation of β-amyloid plaque is the hallmark of AD in the patients’ brain. γ-secretase is thought to contribute to the development of Alzheimer’s disease by generating β-amyloid peptides (Aβ peptides), particularly those that are prone to aggregation such as Aβ42. Aβ peptides are generated through the processing of amyloid precursor protein (APP) by β-secretase and γ-secretase in a stepwise fashion. After the β-secretase enzyme (BACE1, aspartyl protease) cleaves the APP extracellular domain, γ-secretase cleaves the remaining part to release the Aβ peptide and the AICD (App intracellular domain).The AICD will regulate the calcium signal in the nucleus. And The Aβ peptides can aggregate into small neurotoxic oligomeric structures (App oligomers) and eventually form the typical plaques seen in Alzheimer’s disease. γ-secretase cleaves APP at different positions, possibly in a consecutive way, resulting in the release of Aβ peptides that ranged from 37 to 49 amino-acid residues. Aβ40 is the most abundant product cleaved and is found in the artificial cerebrospinal fluid and the plasma. Aβ42 occurs less usually and only account for 10 % of the Aβ40 in the organism. But Aβ42 is considered pathogenic, it aggregates faster than Aβ40 and is more toxic to the cells. The mutations of subunit PS in the γ-secretase always cause the relative amount of Aβ42 and Aβ40, whose ratio was usually regarded as an indicator of pathogenic mutations. So γ-secretase, especially the PS domain is considered as the drug target in screening of drugs for AD therapy.

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