Aspartic proteases involved in Alzheimer's disease.
Alzheimer's disease afflicts every tenth human aged over 65. Despite the dramatic progress that has been made in understanding the disease, the exact cause of Alzheimer's disease is still unknown. Most gene mutations associated with Alzheimer's disease point at the same culprits: amyloid precursor protein and ultimately amyloid beta. The enigmatic proteases alpha-,beta-, and gamma-secretase are the three executioners of amyloid precursor protein processing, and disruption of their delicate balance is suspected to result in Alzheimer's disease. Significant progress has been made in the selective control of these proteases, regardless of the availability of structural information. Not even the absence of a robust cell-free assay for gamma-secretase could hamper the identification of nonpeptidic inhibitors of this enzyme for long. Within five years, four distinctly different structural moieties were developed and the first drug candidates are in clinical trials. Unfortunately, selective inhibition of amyloid beta formation remains a crucial issue because fundamental fragments of the gamma-secretase complex are important for other signaling events. This problem makes beta-secretase inhibition and alpha-secretase induction even more appealing.
Schmidt
Boris
B
Clemens-Schöpf-Institute for Organic Chemistry and Biochemistry TU Darmstadt, Petersenstrasse 22 64287 Darmstadt, Germany. schmibo@oc.chemie.tu-darmstadt.de
D000544:Alzheimer Disease / Q000201:enzymology*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015415:Biomarkers / Q000737:chemistry; D002986:Clinical Trials as Topic; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human