Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer's disease. Thus, beta- and gamma-secretases, that are involved in the Abeta generation, are plausible molecular targets for Alzheimer's disease treatment. gamma-Secretase is an unusual aspartic protease that cleaves the scissile bond within ...

The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the approximately 4.5 kDa protein fragment called Abeta (amyloid beta-peptide). Abeta is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as beta- and gamma-secretase. beta-Secretase is of central importance, as it c...

g-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Ab) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). Despite considerable interest in developing g-secretase targeting therapeutics for the treatment of AD, the precise mechanism by which g-secretase produces Ab has remained elusi...

I. The Alzheimer Disease Puzzle 466 A. The amyloid cascade hypothesis 466 B. Moving towards more comprehensive theories for AD 466 C. The importance of tau 467 II. Proteolysis Involved in Multiple Scenarios for Alzheimer Disease 467 A. Proteolytic processing of the APP 467 B. General disturbances of the endolysosomal-phagocytotic system in AD neurons 468 III. Heterogeneity of the Amyloid A Pept...

-Secretase is a membrane protein complex that cleaves the -amyloid precursor protein (APP) within the transmembrane region, after prior processing by -secretase, producing amyloid -peptides A 40 and A 42. Errant production of A -peptides that substantially increases A 42 production has been associated with the formation of amyloid plaques in Alzheimer’s disease patients. Biophysical and genetic...

γ-secretase is a large ubiquitously expressed protease complex composed of four core subunits: presenilin, Aph1, PEN-2, and nicastrin. The function of γ-secretase in the cells is to proteolytically cleave various proteins within their transmembrane domains. Presenilin and Aph1 occur as alternative variants belonging to mutually exclusive γ-secretase complexes and providing the complexes with he...

Alzheimer's disease (AD) is the most prevalent form of dementia affecting the elderly. Neurodegeneration is caused by the amyloid beta (Aβ) peptide which is generated from the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by the β- and γ- secretases. Previous reports revealed that the 37 kDa/67 kDa laminin receptor (LRP/LR) is involved in APP processing, however, the ex...

Accumulation and deposition of amyloid-β peptide (Aβ) in the brain is a primary cause of the pathogenesis of Alzheimer's disease (AD). Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase. Inhibiting β-secretase activity is believed to be one of the most promising strategies for AD treatment. In the present study, we fo...

One characteristic feature of Alzheimer’s disease is the deposition of amyloid -peptide (A ) as amyloid plaques within specific regions of the human brain. A is derived from the amyloid -peptide precursor protein ( -APP) by the intramembranous cleavage activity of -secretase. Studies in cells have revealed that -secretase is a large multimeric membrane-bound protein complex that is functionally...

Gamma-secretase is a multiprotein, intramembrane-cleaving protease with a growing list of protein substrates, including the Notch receptors and the amyloid precursor protein. The four components of gamma-secretase complex--presenilin (PS), nicastrin (NCT), Pen2, and Aph1--are all thought to be essential for activity. The catalytic domain resides within PS proteins, NCT has been suggested to be ...