Regulation of serine protease activity by aluminum: implications for Alzheimer disease.

Abstract

The brain of Alzheimer disease patients contains plaques that are diagnostic for the disease. The plaques also contain (-amyloid peptide, a1-antichymotrypsin, and the element aluminum. We present indirect evidence that can relate all three components of plaques to each other in such a way as to suggest their involvement in the etiology of the disease. The P-amyloid peptide is derived by proteolytic processing from 3-amyloid precursor proteins and some of these proteins contain a domain that is highly homologous to bovine pancreatic trypsin inhibitor. Bovine pancreatic trypsin inhibitor also inhibits a-chymotrypsin and we show that aluminum affects both the activity and the inhibition ofthis enzyme. At pH 6.5, in the presence of aluminum, the enzyme activity is doubled, and the inhibitor is only 1% as effective as in the absence of the metal ion. The inhibition by BX-9, a protease inhibitor prepared from protein components of amyloid plaques, is also reduced by aluminum; so too is that by ar-antichymotrypsin but to a lesser degree. In the Alzheimer brain, we propose that aluminum may accelerate proteolytic processing of the P-amyloid precursor protein by suppression of the inhibitor domain. Thus, the 8-amyloid peptide may accumulate and initiate plaque formation.Increased levels of aluminum have been observed in neuritic deposits, the plaques and the neurofibrillary tangles, of Alzheimer disease (AD) (1) and amyotrophic lateral sclerosis (2). Several in vitro studies have demonstrated the neurotoxicity of aluminum (3). Recent epidemiological evidence associates increased bioavailability ofaluminum with incidence of AD (4). Because the solution chemistries of aluminum and iron are very similar (5), the observed slow accumulation of aluminum in brain and bone tissue is suggested to occur via the iron transport and storage systems (3). Despite the in vivo and in vitro evidence, no initial event(s) for the involvement of aluminum in AD or amyotrophic lateral sclerosis has been established. Therefore, some researchers have questioned (35) the importance or the role of aluminum in the early pathogenesis of these neurological disorders.By contrast, the /3-amyloid peptide found at the "heart" of AD plaques remains a consistent feature ofAD (6, 7). Recent discoveries of B-amyloid mutations in some cases of earlyonset familial AD further underscore the importance of 3-amyloid peptide in the etiology of AD (8). The P-amyloid peptide(s) has 39-43 amino acids and is part of the family of 3-amyloid precursor proteins that contain 695, 751, and 770 amino acids that upon proteolysis generate the 83-amyloid peptide(s). The two larger precursors (751 and 770 amino acids long) also contain a 56-amino acid segment whose sequence is >60% homologous to the bovine pancreatic trypsin inhibitor (bPJI). This discovery suggested the possible role ofthe inhibitor segment in regulating the proteolytic processing of the precursor proteins to generate f3-amyloid peptide(s). However, the pool of f3-amyloid protein precursors is neither ...

Aluminium in Alzheimer?s disease: are we still at a crossroad?

“…Al, a non-transition metal, is also known to enhance the processing of APP. It has been shown by Clauberg and Joshi [79] that Al accumulated in AD brain accelerates the generation of Ab due to the faulty proteolysis of normal APP [79]. It has been shown that APP has a domain homologous to bovine pancreatic trypsin inhibitor, and the activity of serine protease inhibitors is inhibited by Al.…”

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“…Most resorbed aluminum is excreted; the non-excreted part is largely deposited in bone. Some resorbed aluminium leaks slowly into the cells and may interfere with the transcription of DNA (Lukiw et al 1992), increase the production of beta-amyloid from the amyloid precursor protein (Clauberg andJoshi 1993, Zatta et al 1993). induce aggregation of the beta-amyloid (Mantyh et al 1993, Kawahara et al 1994, Exley et al 1995 and contribute to the formation of neurofibrillary tangles (Shin et al 1995, Zatta 1995.…”

Aluminium - Non-Essential Activator of Pepsin: Kinetics and Thermodynamics

“…The obtained activation of pepsin is probably a consequence of conformational changes of enzyme molecule induced by bounded aluminium. As it were previously reported in analogy to the other aspartic proteases, bounded aluminium ions could causes significant conformational changes and induce increase in beta structure content (Flaten et al 1992, Bittar et al 1992, Clauberg et al 1993). …”