Inhibition of ??-Secretase as a Therapeutic Intervention for Alzheimer???s Disease

Abstract

Genetic and experimental evidence points to amyloid-beta (Abeta) peptide as the culprit in Alzheimer's disease pathogenesis. This protein fragment abnormally accumulates in the brain cortex and hippocampus of patients with Alzheimer's disease, and self-aggregates to form toxic oligomers causing neurodegeneration.Abeta is heterogeneous and produced from a precursor protein (amyloid precursor protein [APP]) by two sequential proteolytic cleavages that involve beta- and gamma-secretases. This latter enzyme represents a potentially attractive drug target since it dictates the solubility of the generated Abeta fragment by creating peptides of various lengths, namely Abeta(40) and Abeta(42), the longest being the most aggregating. gamma-Secretase comprises a molecular complex of four integral membrane proteins - presenilin, nicastrin, APH-1 and PEN-2 - and its molecular mechanism remains under extensive scrutiny. The ratio of Abeta(42) over Abeta(40) is increased by familial Alzheimer's disease mutations occurring in the presenilin genes or in APP, near the gamma-secretase cleavage site. Potent gamma-secretase inhibitors have been identified by screening drug libraries or by designing aspartyl protease transition-state analogues based on the APP substrate cleavage site. Most of these compounds are not specific for gamma-secretase cleavage of APP, and equally inhibit the processing of other gamma-secretase substrates, such as Notch and a subset of cell-surface receptors and proteins involved in embryonic development, haematopoiesis, cell adhesion and cell/cell contacts. Therefore, current research aims at finding compounds that show selectivity for APP cleavage, and particularly that inhibit the formation of the aggregating form, Abeta(42). Compounds that target the substrate docking site rather than the enzyme active site are also being investigated as an alternative strategy. The finding that some NSAID analogues preferentially inhibit the formation of Abeta(42) over Abeta(40) and do not affect Notch processing has opened a new therapeutic window. The progress in design of selective inhibitors as well as recent results obtained in animal studies prove that gamma-secretase remains among the best targets for the therapeutic control of amyloid build-up in Alzheimer's disease. The full understanding of gamma-secretase regulation may yet uncover new therapeutic leads.

BRI2 Inhibits Amyloid β-Peptide Precursor Protein Processing by Interfering with the Docking of Secretases to the Substrate

“…This mechanism of inhibition of amyloid formation by BRI2 suggests an alternative therapeutic approach to AD aimed at inhibiting access of secretases to APP rather than the activity of secretases. This method would avoid toxic effects caused by inhibiting processing of other substrates of secretases (Evin et al, 2006) or even a direct pathogenic effect of ␥-secretase inhibitors, as postulated by others (Saura et al, 2004;Shen and Kelleher, 2007). These findings raise the valid concern 4.…”

BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2

“…This method would represent an alternative therapeutic approach to AD, which would avoid toxic effects due to inhibiting processing of other substrates of secretases (42) or even a direct pathogenic effect of ␥-secretase inhibitors, as postulated by others (43,44). Evidence that the transgenic expression of BRI2 reduces APP processing (21) and amyloid pathology in mouse models of AD (21, 41) supports this notion.…”

The Mitochondrial Secret(ase) of Alzheimer's Disease

“…Their anti-inflammatory nature makes NSAIDS a potential therapeutic against the AD-associated elevations in activated microglia and inflammatory cytokines. Some NSAIDs (e.g., ibuprofen, fluriprofen, and indomethacin) also possess the ability to reduce Aβ 42 levels by modulating γ-secretase activity to preferentially generate the shorter, less amyloidogenic peptide Aβ 38 [115][116][117][118]. The γ-secretase modulating feature of NSAIDs does not affect other targets of γ-secretase activity (i.e., Notch and other AβPP cleavage products) and is thought to act synergistically with its anti-inflammatory effects; therefore, this was a promising step for AD therapy.…”