Secretase Inhibitors
Deposition of Aβ is an early event in the pathogenesis of Alzheimer's disease (AD). The β-amyloid gene, located on chromosome 21, encodes a transmembrane amyloid precursor protein (APP), which gives rise to Aβ. In normal healthy individuals, Aβ peptides are present only in small quantities as soluble monomers that circulate in the cerebrospinal fluid and blood. However, in AD patients, the level of Aβ peptides is significantly increased and they begin to accumulate as insoluble, fibrillar plaques.
Processing of APP in vivo occurs by two major pathways. Cleavage of APP at the N-terminus of the Aβ region by β-secretase and at the C-terminus by γ-secretases represents the amyloidogenic pathway for processing of APP. β-secretase cleaves APP between residues Met671 and Asp672 and yields Aβ peptide plus the C99 fragment. Following β-secretase cleavage, a second cleavage occurs at the C-terminus of Aβ peptide that releases Aβ from C99. This cleavage occurs in the vicinity of residue 712 of the C-terminus. γ-secretase can cleave the C-terminal region at either Val711 or Ile713 to produce a shorter Aβ peptide (Aβ1-40) or the longer Ab peptide (Aβ1-42). The predominant form of Aβ found in the cerebrospinal fluid is the shorter Aβ40 peptide. Despite its lower rate of synthesis, Aβ42 is the peptide that is initially deposited within the extracellular plaques of AD patients. In addition, Aβ42 is shown to aggregate at a much lower concentration than the Aβ40 form.
APP can also be processed by α-secretase (TACE), which cleaves within the Aβ domain between Lys687 and Leu688 and produces a large soluble α-APP domain and the C-terminal fragment containing P3 and C83. The latter can then be cleaved by γ-secretase at residue 711 or 713 to release the P3 fragment. This pathway does not yield Aβ peptide. Hence, shunting APP towards the α-secretase pathway may have a beneficial effect in lowering Aβ peptide levels.
The characterization of APP secretases during the past few years has provided significant advancement in therapeutic strategies that may lead to limiting the build up of Aβ peptide in the brain and eliminate or delay the pathological effects of AD. Recent characterization of secretases has uncovered several common features, particularly their sensitivity to certain metalloproteinase inhibitors and up-regulation of their activity by phorbol esters. Presenilins and γ-secretases are considered to be the best molecular targets for developing therapeutic agents that may minimize the debilitating effects of AD. Major targets in AD research are identifying the genetic and environmental factors responsible for β-amyloid build-up in nerve cells.
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