Inhibitor SourceBook™ Second Edition

Secretase Inhibitors
Deposition of Ab is an early event in the pathogenesis of
Alzheimer's disease (AD). The b-amyloid gene, located
on chromosome 21, encodes a transmembrane amyloid
precursor protein (APP), which gives rise to Ab. In
normal healthy individuals, Ab 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 Ab 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 Ab region
by b-secretase and at the C-terminus by g-secretases
represents the amyloidogenic pathway for processing of
APP. b-secretase cleaves APP between residues Met 671
and Asp 672 and yields Ab peptide plus the C99 fragment.
Following b-secretase cleavage, a second cleavage occurs
at the C-terminus of Ab peptide that releases Ab from C99.
This cleavage occurs in the vicinity of residue 712 of the
C-terminus. g-secretase can cleave the C-terminal region
at either Val 711 or Ile 713 to produce a shorter Ab peptide
(Ab 1-40 ) or the longer Ab peptide (Ab 1-42 ). The predominant
Calbiochem • Inhibitor SourceBook
Neurobiology/Neurodegeneration
form of Ab found in the cerebrospinal fluid is the shorter
Ab 40 peptide. Despite its lower rate of synthesis, Ab 42 is the
peptide that is initially deposited within the extracellular
plaques of AD patients. In addition, Ab 42 is shown to
aggregate at a much lower concentration than the Ab 40
form.
APP can also be processed by a-secretase (TACE), which
cleaves within the Ab domain between Lys 687 and Leu 688
and produces a large soluble a-APP domain and the Cterminal
fragment containing P3 and C83. The latter can
then be cleaved by g-secretase at residue 711 or 713 to
release the P3 fragment. This pathway does not yield Ab
peptide. Hence, shunting APP towards the a-secretase
pathway may have a beneficial effect in lowering Ab
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 Ab 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 g-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 b-amyloid build-up in nerve cells.
References:
Tomita, T. and Iwantsubo, T. 2006. Curr. Pharm. Res. 12, 66 .
Steiner, H., et al. 2004. Curr. Alzheimer Res. 1, 75.
Marlow, L., et al. 2003. J. Mol. Neurosci. 20, 233.
Wilson, C.A., et al. 2003. J. Neurosci. Res. 74, 36 .
Li, Y-M. 200 . Mol. Interv. 1, 98.
Selkoe, D.J. 200 . Physiol. Rev. 81, 74 .
Li, Y-M., et al. 2000. Nature 405, 689.
Zhang, Z., et al. 2000. Nat. Cell Biol. 2, 463.
Haass, C., and De Stooper, B. 999. Science 286, 9 6,
Sinha, S., and Lieberburg, I. 999. Proc. Natl. Acad. Sci. USA 96, 049.
Chen, M. 997. FEBS Lett. 417, 63.
Selkoe, D. J. 997. Science 275, 630.
Schweuner, D., et al. 996. Nat. Med. 8, 864.
Citron, M., et al. 994. Proc. Natl. Acad. Sci. USA 91, 993.
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