The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). APP can undergo two exclusive proteolytic pathways: cleavage by the α-secretase initiates the non-amyloidogenic pathway while cleavage by the β-secretase initiates the amyloidogenic pathway that leads, after a second cleavage by the γ-secretase, to amyloid-β (Aβ) peptides that can form toxic extracellular depo...

The phosphotyrosine binding domain of the neuronal protein X11a/mint-1 binds to the C-terminus of amyloid precursor protein (APP) and inhibits catabolism to b-amyloid (Ab), but the mechanism of this effect is unclear. Coexpression of X11a or its PTB domain with APPswe inhibited secretion of Ab40 but not APPsbswe, suggesting inhibition of cbut not b-secretase. To further probe cleavage(s) inhibi...

Amyloid precursor protein (APP) secretase plays a pivotal role in the processing of APP since its activity precludes the formation of amyloid peptide in Alzheimer's Disease. The identity and the subcellular localization of this enzyme are at this moment unknown. It is also unclear how APP escapes the activity of this enzyme when amyloid is formed. We have previously shown that APP-secretase act...

TMP21 has been shown to be associated with the gamma-secretase complex and can specifically regulate gamma-cleavage without affecting epsilon-mediated proteolysis. To explore the basis of this activity, TMP21 modulation of gamma-secretase activity was investigated independent of epsilon-cleavage using an amyloid-beta precursor proteinepsilon (APPepsilon) construct which lacks the amyloid intrac...

The gamma-secretase complex, consisting of presenilin, nicastrin, presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1) cleaves type I integral membrane proteins like amyloid precursor protein and Notch in a process of regulated intramembrane proteolysis. The regulatory mechanisms governing the multistep assembly of this "proteasome of the membrane" are unknown. We characteriz...

Nicastrin is a type I transmembrane glycoprotein, which is part of the high molecular weight γ-secretase complex. γ-Secretase is one of the key players associated with the generation of Alzheimer's disease pathology, since it liberates the neurotoxic amyloid β-peptide. Four proteins Nicastrin, anterior pharynx-defective-1 (Aph-1), presenilin enhancer-2 (Pen-2) and Presenilin are essential to fo...

Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and gamma-secretase to release amyloid peptides (Abeta40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Abeta40/42 is generated by gamma-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in...

γ-Secretase proteases have been associated with pathology in Alzheimer disease (AD), but we are just beginning to understand their basic mechanisms and physiological roles. A negative drug trial with a broad spectrum γ-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing γ-secretase research therapeutically. This pessimism is unwarranted: analysis of...

Epidemiological studies indicate that long term use of nonsteroidal anti-inflammatory drugs (NSAIDs) confers protection from Alzheimer's disease, and some NSAIDs were shown to specifically decrease production of the amyloidogenic Abeta42 peptide, most likely by direct modulation of gamma-secretase activity. In contrast to gamma-secretase inhibitors, Abeta42-lowering NSAIDs do not impair S3 clea...