Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation.

Abstract

The major component of the cerebral plaques in Alzheimer disease is the j3-amyloid peptide, but serine proteinase inhibitors like cvl-antichymotrypsin (ACT) are also present. Their role in the pathogenesis of amyloid formation is unsettled. In addition to their function as proteinase inhibitors, serine proteinase inhibitors can interact with various hydrophobic compounds, a reaction accompanied by a transition from the stressed to the relaxed conformation. We report here on the ability of ACT to regulate the formation of j3-amyloid fibrils in vitro. In a molar ratio of 1:10 (ACT to f8-amyloid) ACT inhibits ,3-amyloid fibril formation. Furthermore, ACT promotes rapid disaggregation of f8-amyloid fibrils when added in the same molar ratio to preformed ,8-amyloid fibrils. These processes are accompanied by increased thermostability of ACT and loss of its biological activity, consistent with a conformational transition of ACT from the stressed to the relaxed state. The influence of ACT on f3-amyloid fibril formation may be an example of a hydrophobic interaction between the j3-amyloid peptide and the hydrophobic domain C terminal to the reactive center of ACT.Alzheimer disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of extracellular congophilic plaques in the brain (1). The main constituent of senile plaques is a 39-to 43-amino acid peptide, called 13-amyloid, which is a proteolytic fragment of the amyloid precursor protein (2). The metabolism of amyloid precursor protein is only partially understood. The proteases responsible for amyloid precursor protein processing and the sites in the brain where these proteolytic events occur are unknown (3). Recently, it was demonstrated that ,B-amyloid is a product of normal cellular metabolism (4-6). Different lengths of the peptide exist, but the major form is 40-42 amino acids, which in solution exist in a monomeric a-helical conformation. In vitro studies have shown that changes in pH, concentration, and temperature result in conformational rearrangements from an a-helix to an oligomeric 13-sheet, which precipitates from solution and produces amyloid-like deposits (7). f3-Amyloid is thought to be important early in the pathogenesis of AD (L.L., unpublished data).Serine proteases and their inhibitors like a1-antichymotrypsin (ACT) and ai-proteinase inhibitor have been identified in different types of amyloid fibril isolates (8). The presence of these proteins in the extracellular amyloid deposits suggests a number of potential roles they may play in the pathogenesis of AD. Recently, it has been shown that a specific sequence within the N-terminal 10 amino acid residues of the f3-amyloid peptide is responsible for the formation of an ACT-amyloid complex (9). These authors also noted that ACT induced fibril disaggregation in vitro. The increased expression of ACT by astrocytes in areas of Alzheimer lesions in the brain known to have many neuritic plaques support such a role (9).Understanding how a normally soluble protein is transform...

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

“…125,130 This ability to interact with a variety of molecules presents a difficulty when attempting to measure Ab levels in biological fluids as the antigenic epitopes may be masked by these bound molecules. 131,132 The interaction of Ab with these binding proteins has been shown to modulate the formation of Ab fibrils 127,128,130 and the binding of Ab complexes to the LRP-1 receptor. Therefore, plasma Ab-binding proteins may have a dual function by reducing the formation of toxic oligomers and fibrils and by enhancing the clearance and degradation of Ab peptides through LRP-1-mediated endocytosis.…”

“…The nature of the Ab peptide gives it the capacity to interact with a variety of plasma proteins including albumin, 125 a2M, 126,127 a1-antichymotrypsin (ACT), 128 serum amyloid P component (SAP), 129 complement proteins, transthyretin, apoferritin, apolipoproteins and lipoproteins. 125,130 This ability to interact with a variety of molecules presents a difficulty when attempting to measure Ab levels in biological fluids as the antigenic epitopes may be masked by these bound molecules.…”

Molecular basis for insulin fibril assembly

“…For example, ␣ 1 -antichymotrypsin, when incubated with A␤ peptides at ratios lower than 1:100, accelerates A␤ fibrillation (36). However, when the ␣ 1 -antichymotrypsin to A␤1-40 ratio is raised to 1:10, fibril formation is inhibited (37). Apoliprotein E4 (Apo E4) is another example in which fibrillation of A␤ peptide is both inhibited and accelerated.…”

Perlecan Binds to the β‐Amyloid Proteins (Aβ) of Alzheimer's Disease, Accelerates Aβ Fibril Formation, and Maintains Aβ Fibril Stability

“…Similarly, previous studies have suggested that a1-antichymotrypsin can either promote (Ma et al, 1994) or inhibit (Fraser et al, 1993;Eriksson et al, 1995) A/I amyloid fibril assembly. Our findings indicated that cr1-antichymotrypsin was a good inhibitor of A/I (1-40) fibril formation.…”