Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-beta(1-40), alpha-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases.

A pathological hallmark in brain tissue from patients with Alzheimer's disease (AD) 1 is the accumulation of amyloid ␤ protein (A␤P), a 39 -43-amino acid-long polypeptide, as morphologically heterogeneous neuritic plaques and cerebrovascular deposits (1, 2). A␤P is derived primarily from a proteolytic cleavage of the ␤-amyloid precursor protein (A␤PP), a highly conserved and widely expressed integral membrane protein with a single membrane-spanning polypeptide. The amount and the nature of polypeptides vary considerably among various forms of ADs: A␤P 1-40 and A␤P 1-42 are differentially accumulated in sporadic Alzheimer's disease and non-demented brain samples (3) and a mutation in presenilins is linked with an increased ratio of A␤P 1-42 /A␤P 1-40 in familial Alzheimer's disease (4 -7). The early-onset familial AD has been correlated with an increased level of A␤P 1-42 . However, very little is known about the role of A␤P 1-42 in such pathology and about the mechanism(s) of its action.Accumulating evidence suggests an early and causative role of A␤Ps in the pathogenic cascade (8 -11). Postulated mechanisms of A␤P toxicity include, by its interaction with the tachykinin neuropeptide system, a surface membrane effect (12); by changing cellular ionic concentration via formation of plasma membrane channels (13-15); and by activating oxidative pathways and making cells more responsive to oxidative stress (for review see Refs. 16 and 17). Reactive oxygen species and the antioxidant defenses work probably by altering the lipid peroxidation and membrane composition. However, A␤P polypeptides associated with the reactive oxygen hypothesis have produced conflicting effects on cytoskeletal organization and cell lysis (18 -23).The commonly observed change in the cellular ion concentration involves increased calcium level (24 -26) either indirectly via modulating the existing Ca 2ϩ channel or directly via cation-selective channels formed by A␤Ps. Support for the cation-selective A␤P channels are accumulating. Arispe and his collaborators (13-15, 27) have reported cation-selective channels formed by A␤P 1-40 when reconstituted into lipid bilayers and in the membrane patches excised from hypothalamic gonadotropin-releasing hormone neurons. Kagan and his collaborators (28) have also recorded channel-like activity when A␤P [25][26][27][28][29][30][31][32][33][34][35] was reconstituted in lipid bilayers as well as for both A␤P 1-40 and A␤P 1-42 reconstituted in lipid bilayer, 2 though, with less reliability and reproducibility than the A␤P 25-35 current (28). Whether A␤P 1-42 toxicity is also mediated via A␤P 1-42 forming calcium-permeable ion channel is unclear.The molecular structure of A␤P oligomers, especially as an ion channel, is unknown. Durell et al. (29) have developed theoretical models for the structure of ion channel formed by the membrane-bound A␤P 1-40 . However, no direct structural data from EM, NMR, x-ray diffraction, or other microscopic techniques are available to support the presence of the A␤P channel.We h...