EMD - Calbiochem - Inhibitors: Neurobiology/Neurodegeneration

		Technical Resources

		Technical Information

		Calbiochem Information

		Inhibitor Resource

		Neurobiology

		Amyloidogenesis
		Cholinesterase
		Monoamine Oxidase
		Secretase

Neurobiology/Neurodegeneration: Secretase Inhibitors

�

Secretase Inhibitors/Blockers of Aβ Production� I 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 Met⁶⁷¹ and Asp⁶⁷² 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 Val⁷¹¹ or Ile⁷¹³ to produce a shorter Ab peptide (Ab_1-40) or the longer Ab peptide (Ab_1-42). The predominant form of Ab found in the cerebrospinal fluid is the shorter Ab₄₀ peptide. Despite its lower rate of synthesis, Ab₄₂ is the peptide that is initially deposited within the extracellular plaques of AD patients. In addition, Ab₄₂ is shown to aggregate at a much lower concentration than the Ab₄₀ form.

APP can also be processed by a-secretase (TACE), which cleaves within the Ab domain between Lys⁶⁸⁷ and Leu⁶⁸⁸ 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:	Visit our Alzheimers Disease Interactive Pathway
Marlow, L., et al. 2003. J. Mol. Neurosci. 20, 233.
Wilson, C.A., et al. 2003. J. Neurosci. Res. 74, 361.
Marlow, L., et al. 2003. J. Mol. Neurosci. 20, 233.
Wilson, C.A., et al. 2003. J. Neurosci. Res. 74, 361.
Li, Y-M. 2001. Mol. Interv. 1, 198.
Selkoe, D.J. 2001. Physiol. Rev. 81, 741.
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. 1999. Science 286, 916,
Sinha, S., and Lieberburg, I. 1999. Proc. Natl. Acad. Sci. USA 96, 11049.
Chen, M. 1997. FEBS Lett. 417, 163.
Selkoe, D. J. 1997. Science 275, 630.
Schweuner, D., et al. 1996. Nat. Med. 8, 864.
Citron, M., et al. 1994. Proc. Natl. Acad. Sci. USA 91, 11993.

�

Table 1: Secretase Inhibitors/Blockers of Aβ Production

Product	Cat. No.	Cell Permeable	Reversible	Comments
APP-b-Secretase Inhibitor	171601	–	√	A substrate analog inhibitor of BACE (IC₅₀ = 30 nM).
Calpain Inhibitor I	208719	√	√	A peptide aldehyde based calpain inhibitor that blocks Ab and p3 secretion. Acts as a g-secretase inhibitor (IC₅₀ ~ 5-200 mM in APP transfected cells). Displays biphasic effect on Ab secretion. Inhibits the secretion of Ab₄₀ to a greater extent than Ab₄₂. At low concentration, shown to increase Ab₄₀ and Ab₄₂ levels and at high concentrations, it lowers Ab₄₀ and Ab₄₂ levels.
Calpain Inhibitor III	208722	√	√	Displays properties similar to Calpain Inhibitor I (Cat. No. 208719). Also affects the processing of Notch.
Calpeptin	03-34-0051	√	√	Displays properties similar to Calpain Inhibitor I (Cat. No. 208719).

View complete table

�

Inhibitors: b-Secretase

View all b-Secretase products

�

Inhibitors: g-Secretase

View all g-Secretase products

�

top of page