BACE and gamma-secretase characterization and their sorting as therapeutic targets to reduce amyloidogenesis.
Secretases are named for enzymes processing amyloid precursor protein (APP), a prototypic type-1 membrane protein. This led directly to discovery of novel Aspartyl proteases (beta-secretases or BACE), a tetramer complex gamma-secretase (gamma-SC) containing presenilins, nicastrin, aph-1 and pen-2, and a new role for metalloprotease(s) of the ADAM family as a alpha-secretases. Recent advances in defining pathways that mediate endosomal-lysosomal-autophagic-exosomal trafficking now provide targets for new drugs to attenuate abnormal production of fibril forming products characteristic of AD. A key to success includes not only characterization of relevant secretases but mechanisms for sorting and transport of key metabolites to abnormal vesicles or sites for assembly of fibrils. New developments we highlight include an important role for an 'early recycling endosome' coated in retromer complex containing lipoprotein receptor LRP-II (SorLA) for switching APP to a non-amyloidogenic pathway for alpha-secretases processing, or to shuttle APP to a 'late endosome compartment' to form Abeta or AICD. LRP11 (SorLA) is of particular importance since it decreases in sporadic AD whose etiology otherwise is unknown.
Marks
Neville
N
Center for Neurochemistry, Nathan S Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. marks@nki.rfmh.org
Berg
Martin J
MJ
D051722:ADAM Proteins / Q000502:physiology; D000544:Alzheimer Disease / Q000503:physiopathology; D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D057055:Aspartic Acid Proteases / Q000378:metabolism; D001343:Autophagy / Q000502:physiology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000503:physiopathology; D015195:Drug Design; D010450:Endopeptidases; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases; D053763:Presenilins / Q000235:genetics; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D013379:Substrate Specificity
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C469349:PSENEN protein, human; D053763:Presenilins; C413604:nicastrin protein; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D057055:Aspartic Acid Proteases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins