Author: Harald Steiner

Source: Current Alzheimer Research, Volume 1, Number 3, August 2004 , pp. 175-181(7)

Publisher: Bentham Science Publishers

Abstract:

Accumulation of the amyloid -peptide (A) in the brain is believed to initiate a series of neurotoxic events that causes neurodegeneration in Alzheimer´s disease (AD). A is generated by processing of the -amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, -secretase and -secretase. While -secretase has been identified as the membrane-bound aspartyl protease BACE, the identity of -secretase, which catalyzes the final, intramembrane cleavage of APP as well as of several other type I transmembrane proteins, has been enigmatic for a long time. Exciting progress has been made in the past year towards its uncovering. Genetics paved the way for subsequent biochemical reconstitution studies that demonstrated that -secretase is a protein complex composed of presenilin (PS), nicastrin (NCT), APH-1 and PEN-2. Thus, the complete set of genes that is required to generate A from its precursor has now ultimately been identified. PS carries the active site of -secretase and is a founding member of a novel class of polytopic aspartyl proteases that utilize a non-classical active site to cleave their membrane-tethered substrates. The other components are required for assembly, stabilization and maturation of the complex and NCT may be involved in the recognition of -secretase substrates.

Keywords: alzheimer's disease; amyloid peptide; aph-1; nicastrin; nicastrin; pen-2; presenilin; secretase; secretase complex

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1567205043332081

Affiliations: 1: Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Schillerstr. 44, Ludwig-Maximilians-University, 80336 Munich, Germany.

Publication date: 2004-08-01

More about this publication?

• Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

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