... from the proteolytic processing of amyloid precursor protein (APP) by sequential cleavage mediated via β- and γ-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Aβ levels which, in turn, contribute to neuronal loss and development of AD. Objectives...

... demonstrated that purified mutant PS1/γ-secretases also increase the Aβ42 ratio in de novo Aβ [ 2 ]. Since substantial amounts of Aβ42 accumulate in brains of FAD patients with PS1 mutations (PS1-FAD patients), it is easy to assume that the accumulation is caused by increased Aβ42 secretion in the brain...

...Jie Shen The presenilin (PS) genes harbor approximately 90% of the identified mutations linked to familial forms of Alzheimer's disease, and the presenilin (PS) proteins are essential components of the γ-secretase complex involved in the proteolytic cleavage of type I receptors, such as Notch...

... to γ-secretase inhibitor treatment. In a clinical trial including AD patients, Aβ1–14, Aβ1–15, and Aβ1–16 increased dose-dependently in response to treatment with the γ-secretase inhibitor LY450139. In dogs, Aβ1–37 was significantly increased in response to treatment with the γ-secretase modulator...

...Julie Hawkins; David C. Harrison; Sharlin Ahmed; Robert P. Davis; Trevor Chapman; Ian Marshall; Beverley Smith; Tania L. Mead; Andrew Medhurst; Ged M.P. Giblin; Adrian Hall; Maria I. Gonzalez; Jill Richardson; Ishrut Hussain Background: Allosteric modulation of γ-secretase is an attractive...

... protein (APP) by β-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-β (Aβ) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch...

... process. Aβ is generated from amyloid precursor protein after sequential cleavage by β- and γ-secretase. Alternatively, α-secretase cleaves within the Aβ sequence, thus, precluding the formation of Aβ. A lot of research has focused on Aβ production, while less is known about the non-amyloidogenic pathway...

... proteolysis by presenilin (PS)/γ-secretase at least at two sites, near the middle of the TM (γ-/S4 cleavage) and at the interface between cytosol and the TM (Ε-/S3 cleavage), releasing Alzheimer disease (AD)-associated β-amyloid (Aβ)/Notch-1β (Nβ) and βAPP intracellular cytoplasmic domain (AICD)/Notch-1...

...Christoph Kaether; Christian Haass; Harald Steiner γ-Secretase catalyzes the final cleavage of the β-amyloid precursor protein to generate amyloid-β peptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer’s disease. Here, we review the identification...

... by the multiprotein complex γ-secretase, which constitutes a prime drug target for prevention and therapy of the disease. However, highly potent γ-secretase inhibitors that block formation of all Aβ peptides have provoked troubling side effects in preclinical animal models of AD. This toxicity can be readily...