Two‐way cleavage of β‐amyloid protein precursor by multicatalytic proteinase

Abstract

The/?-amyloid protein @-AP) derived from a&amyloid protein precursor (APP) is a hallmark of Alzheimcr's disease. The abundant generation oT&AP suggests the abnormal promsing of' APP. but the molecular mechanism remains unclear. The main APP-processing enzyme WRS purified from the ral brain and identi!ied to be a macropain-like multicatalytic proleinasc. The purified enzyme clcavcd the Gln'5-Lys'n bond OTB-AP, but altered to cleuve at the N-terminus of&AP to rcleasc the cxtracellLdar domain ofp-AP in the presence of Ca". These findings suggest that the functional change in this multicatalytic protcinasc may result in abnormal processing of APP.P-Amyloid protein prcsursor; Muhicatalylic protcinasc; Macropain: Ral brain; Calcium ion

Processing of the β‐Amyloid Precursor Protein and Its Regulation in Alzheimer's Disease

“…In this context, several proteases have been suggested as potential a-secretase candidates. By means of model peptides or chromogenic substrates, cathepsin B (Tagawa et al, 1991), the multicatalytic proteinase complex (Kojima and Omori, 1992), and a 105-120-kDa metalloprotease isolated from human brain (Mc-Dermott and Gibson, 1991) were shown to mimic a-secretase-like activity. On the other hand, membrane-bound proteases that could account for the membrane-associated counterpart of a-secretase include endopeptidase 3.4.24.11 (Marks et al, 1994), a Ca 2+activated, dithiothreitol-sensitive metalloproteinase present in rat brain cortex (Allsop et al, 1991), a protease activity apparently associated with acetylcholinesterase (Small et al, 1991), and an integral membrane metallopeptidase recently detected in crude membranes prepared from H4 human neuroglioma cells .…”

Ubiquitin- and proteasome-dependent pathway of protein degradation as an emerging therapeutic target

“…Aβ is produced by proteolytic cleavage from amyloid precursor protein (APP) by several poorly defined proteolytic activities, called α, β and γ secretases. The proteasome has been postulated to be responsible for the β [140], γ [141] and α secretase activity [142]. Indeed, different inhibitors of the ChTL activity of the proteasome, including Cbz-VFal (MDL-28170), calpain inhibitor I, Cbz-LLnLal, calpeptin and Cbz-LLLal have been shown to inhibit the secretion of β-amyloid peptide from cultured cells [143][144][145][146].…”

Emerging strategies for the treatment of Alzheimer’s disease at the Millennium

“…The proteasome, a multicatalytic protease found inside cells, appears to have both β-and γ-secretase activity [147][148][149], as has a cathepsin D-like aspartyl protease [150,151].…”