title: Trafficking and proteolytic processing of APP.
abstract: Accumulations of insoluble deposits of amyloid β-peptide are major pathological hallmarks of Alzheimer disease. Amyloid β-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the β-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. β- and γ-secretase liberate by sequential cleavage the neurotoxic amyloid β-peptide, whereas α-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases, 80336 Munich, Germany; Adolf Butenandt-Institute, Biochemistry, Ludwig-Maximilians University, 80336 Munich, Germany. christian.haass@dzne.lmu.de
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaether
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
authors.forename: Sangram
authors.initials: S
authors.lastname: Sisodia
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D059748:Proteolysis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases