Evidence that Perutz's double-β-stranded subunit structure for β-amyloids also applies to their channel-forming structures in membranes

Abstract

Although there is a growing body of evidence that different amyloidoses may have a similar molecular mechanism in common, the many details of this mechanism are not understood. In this study, we propose that there is a common molecular structure of the primary agents of these diseases, namely a small oligomer of Perutz's cylindrical double-␤-stranded subunit for polyglutamine and that this structure, which contains a central water-filled core, can spontaneously integrate into the bilayers of membranes to form aqueous pores. We suggest that this ability to produce permeable channels in appropriate neuronal membranes is a key element in the toxicity of the ␤-amyloids. One strong criterion for the stability of the Perutz structure for an amyloid is that it contain Ϸ40 or more amino acid residues. We show here that the neurotoxic A␤ amyloids 1-40 and 1-42, related to Alzheimer's disease, spontaneously enter the membranes of intact erythrocytes and cause their lysis but that A␤ 1-38 and A␤ 1-35, which are not neurotoxic, have no observable effects on erythrocytes, supporting our proposal. Other aspects of the proposed mechanism of cytotoxicity of the ␤-amyloids are explored.A large and continually increasing number of diseases, including the neurodegenerative syndromes Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease as well as the spongiform encephalopathies (prion diseases) such as mad cow disease are all associated with the formation of characteristic proteinaceous components that can form aggregates and͞or fibrils under appropriate conditions in water. These components are collectively called ␤-amyloids. In these fibrils and aggregates, the ␤-amyloids are all largely in the ␤-conformation and can be stained with Congo red, which reveals that they contain a hydrophobic environment that bonds the dye. These extensively aggregated ␤-amyloid structures are present at equilibrium with small water-soluble species containing from one to a dozen or so of the repeating subunits of the ␤-amyloid, each bonded noncovalently to its neighboring subunits. It is widely accepted that some form of the particular ␤-amyloid is critically involved in the neurotoxicity of its associated disease, but the detailed mechanisms for this involvement have not been elucidated. In previous years, it was vigorously disputed whether the larger aggregates or one or more of the smaller soluble species of ␤-amyloids are the primary toxic components, but in the last few years, several studies (see refs. 1-4) have clearly implicated the smaller soluble species in the toxic process. The fibrils and aggregates may serve as storage depots of longer ␤-amyloid chains rather than of the shorter soluble forms. Close Similarities in the Structures and Functions of Different ␤-AmyloidsOne of the most remarkable of these recent studies is that of Kayed et al. (3). Working with A␤ 1-40, which is a ␤-amyloid associated with AD, Kayed et al. reported the production of a MAb that binds to, and inhibits the toxicity of, water-soluble intermed...

Protection against β-amyloid induced abnormal synaptic function and cell death by Ginkgolide J

“…However, it is hard to compare the two experimental paradigms. Indeed, it has been demonstrated that Aβ peptides with less than 40 amino acids which do not form conducting pores in black lipid bilayer films and in intact cell membranes, are not neurotoxic in cultured hippocampal neurons [44]. Thus, it is possible that the discrepancy with our data is due the different form of Aβ utilized.…”

Heme binding inhibits the fibrillization of amyloidogenic apomyoglobin and determines lack of aggregate cytotoxicity

“…At present, it is hard to find an explanation for this result. Recently, Singer and Dewji (2006) proposed that the common molecular structure responsible for the toxicity of the early oligomeric aggregates of amyloidogenic proteins and peptides is the cylindrically wound double-b-stranded subunit that Perutz et al (2002) derived from the X-ray diffraction studies of polyglutamine fibers. This structure interacts with cell membrane, forming a water-filled channel of about 15 nm in diameter, large enough to permit the diffusion of small ions.…”

Treatment of Alzheimer’s Disease with a Cholinesterase Inhibitor Combined with Antioxidants

“…In this case, the number of patients needed would be much greater. Sickle erythrocytes were studied in relation to amyloid only [41,42] , but theoretically their increase could be detected in many other diseases. Therefore, to draw correct clinical conclusions, more studies will have to be conducted in this area.…”

“…Erythrocytes bind amyloid dimers or trimers [41,42] that generate pore-like structures on the erythrocyte membrane and can alter the cell membrane and volume. They exhibit ionophore-like properties [43] and undergo OS, resulting in an increase in erythrocyte size and the assumption of an elongated shape (sickle erythrocytes).…”