Alzheimer’s Disease

Abstract

Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as Nacetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of ␤-amyloid peptide (A␤) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on A␤ formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of ␤-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress A␤ formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in A␤ formation. Key Words: Alzheimer's disease -Amyloid-␤-Amyloid peptide -Proteasome -Inhibitor. J. Neurochem. 73, 195-204 (1999).The accumulation of the 39 -43-residue ␤-amyloid peptide (A␤) (Glenner and Wong, 1984) in senile plaques and in the walls of cerebral blood vessels is an important pathological feature of Alzheimer's disease. A␤ is derived by proteolytic processing of the ␤-amyloid precursor protein (APP), an integral type 1 membranespanning glycoprotein. There is considerable interest in the proteolytic enzymes involved in this process, as the formation and aggregation of A␤ are likely to be key pathological events in the development of Alzheimer's disease (Hardy and Allsop, 1991). Early studies (Esch et al., 1990;Anderson et al., 1991) showed that the majority of APP is cleaved by ␣-secretase at the Lys 16 -Leu 17 bond in the middle of the A␤ sequence, to produce a large, soluble, N-terminal fragment, which is referred to here as sAPP␣. An alternative pathway of APP processing has been implicated in the formation of A␤, involving an initial cleavage by ␤-secretase at the Met 596 -Asp 597 bond (numbered according to APP-695) to derive the N terminus of A␤ (Seubert et al., 1993), followed by a second ␥-secretase-mediated cleavage within the membrane-spanning domain of APP to release the C terminus of A␤. Several forms of A␤ of different length have been described, with A␤40 and A␤42 being prominent species (see, for example, Asami-Odaka et al., 1995). The longer forms of A␤ seem to be particularly important in the pathogenesis of Alzheimer's disease (Younkin, 1995).The identity of the ␣-, ␤-, and ␥-secretases is unknown, although the effects of various class-specific protease inhibitors suggest that ␣-secretase is a zinc metalloproteinase, with similarities to the angiotensin converting enzyme secretase and other related membrane-associated secretases (Parvathy et al., 1998). As far as ␤-secretase is concerned, the proteasome has been implicated (Ishiura et al., 1989), as have several chymotrypsin-like serine proteinases (Nelson et al., 1993;Sahasrabudhe et al., 1993;Savage et al., 1994), the metallopeptidase thimet (McDermott et al., 1992), and Received November 4, 1...

L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity

“…As the above experiments were carried out in cell-based assays only, the mechanism of action and true molecular targets of these inhibitors could not be specified. A subse- quent more detailed analysis revealed that for peptide aldehyde and boronates, a good correlation exists between inhibition of Aβ formation and inhibition of the chymotrypsin-like activity of the proteasome (25). The exact role of the proteasome in the production and/or secretion of Aβ was not determined in this study, but it draws attention to the complications associated with the use of high concentrations of these compounds as γ-secretase inhibitors in cellbased assays, and casts doubt on the data as evidence of multiple enzymes.…”

Modulatory effect of ursolic acid on neurodegenerative activities in oxidative brain injury: Anex vivostudy

“…Unrestrained proteolysis has been linked to the proliferation of neurotoxic cells which is part of the underlying pathogenesis and progression of most neurodegenerative diseases (Christie et al, 1999;Klegeris & McGeer, 2005). Inhibition of α-chymotrypsin has been reported to be therapeutic against neurodegenerative diseases and has been associated with repressed β-amyloid peptide secretion (Christie et al, 1999;Giunta et al, 2007). The inhibited activity of the enzymes in brain tissues treated with UA, therefore, indicates an anti-proteolytic effect by the triterpenoid.…”

Synapsin-1 and tau reciprocal O-GlcNAcylation and phosphorylation sites in mouse brain synaptosomes

“…These findings are consistent with previous studies in which O -GlcNAcylation of a specific serine residue was found to modulate its regulatory function. 13 Several research groups, including that of Jovanovic et al, report that this neuronal protein regulates synaptic vesicle trafficking through a reciprocal process between phosphorylation and dephosphorylation of specific synapsin-1 sites, 14, 15, 16 and this particular serine residue is reported to be a potential reciprocal site involved in regulating hippocampal synaptic plasticity. 17 We also identified that Ser 692 in the tau peptide sequence 688 SPVVSGDTSPR 698 is a potential reciprocal site in mouse brain synaptosomes.…”