Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process

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 Peptide and the Toxic Oligomer Hypothesis 468 A. A toxicity in Alzheimer disease 468 B. Heterogeneity of the A peptide in vivo and potential contribution to overall toxicity 469 IV. -Secretase and the Physiologically Most Relevant Proteolysis of APP 469 A. -Secretase activity and the generation of APPs and p3 469 B. Members of the ADAM family exert -secretase activity 470 C. Other -secretases 471 D. -Secretase as a Drug Target for AD 471 V. -Secretase 471 A. BACE1 is the major -secretase 471 B. Molecular and cellular biology of BACE1 472 C. Deregulation of BACE1 expression in AD 472 D. BACE1 physiological functions 473 E. BACE1 as a drug target for AD 474 VI. -Secretases 474 A. The different -secretase complexes 474 B. Molecular and cellular biology of the -secretase 475 C. -Secretases proteolytic functions 476 D. Role of -secretase in the generation of carboxy-terminal heterogeneity of A 477 E. -Secretase as a drug target for AD 478 VII. Neurofibrillar Tangles and Tau 478 A. Tangles and the importance of nuclei formation 478 B. Hyperphosphorylation of tau 479 C. Proteolysis of tau and relevance for AD 480 D. Tau as a drug target in AD 480 VIII. Proteolytic Degradation of the Amyloid A Peptide 481 A. Clearance of A from the brain 481 B. Neprilysin 482 C. Endothelin converting enzymes 1 and 2 482 D. Angiotensin converting enzyme 482 E. Insulin degrading enzyme 482 F. Matrix metalloproteases 483 G. Plasmin 483 H. Cathepsin B and cystatin C 483 IX. Conclusion 484