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.

To better understand the physiologic excretion and/or catabolism of circulating peripheral amyloid ␤ (A␤), we labeled human A␤40 (monomeric, with predominant unordered structure) and A␤42 (mixture of monomers and oligomers in ϳ50:50 ratio, rich in ␤-sheet conformation) with either Na 125 I or 125 I-tyramine cellobiose, also known as the cell-trapping ligand procedure, testing their blood clearance and organ uptake in B6SJLF1/J mice. Irrespective of the labeling protocol, the peptide conformation, and the degree of oligomerization, both A␤40 and A␤42 showed a short half-life of 2.5-3.0 min. The liver was the major organ responsible for plasma clearance, accounting for >60% of the peptide uptake, followed by the kidney. In vivo, hepatocytes captured >90% of the radiolabeled peptides which, after endocytosis, were preferentially catabolized and excreted into the bile. Biliary excretion of intact as well as partially degraded A␤ species became obviously relevant at doses above 10 g. The use of biotin-labeled A␤ allowed the visualization of the interaction with HepG2 cells in culture, whereas competitive inhibition experiments with unlabeled A␤ demonstrated the specificity of the binding. The capability of the liver to uptake, catabolize, and excrete large doses of A␤, several orders of magnitude above its physiologic concentration, may explain not only the femtomolar plasma levels of A␤ but the little fluctuation observed with age and disease stages. Alzheimer's disease (AD)1 is the most frequent type of amyloidosis in humans and the commonest form of clinical dementia. Extracellular A␤ amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy as well as intraneuronal neurofibrillary tangles co-exist in the brain parenchyma, being the cognitive areas the most severely affected. A␤, a 39 -42-amino acid-long peptide of unknown biological function, is an internal processing product of a larger type I transmembrane precursor molecule, APP, codified by a single multiexonic gene located on chromosome 21 (reviewed in Ref. 1). A soluble form of A␤ (sA␤) is present in the biological fluids of both normal individuals and AD patients as well as in cytosolic soluble fractions of normal, AD, and Down's syndrome brain homogenates (2-6). Notably, an increased amount of sA␤ has been reported in AD and Down's syndrome brain tissue in comparison to control individuals (7). Although the primary structures of deposited A␤ and sA␤ are indistinguishable, the circulating peptide is predominantly 40 residues long, whereas sA␤42, the major species in parenchymal deposits, is only a minor component of the circulating pool. To the present, it is not clear whether circulating sA␤s reflect systemic production, brain clearance, or both. The blood-brain barrier has the capability to modulate sA␤ brain uptake and clearance by controlling the uptake of circulating sA␤, either in its free form or bound to its transport apolipoproteins, as well as the elimination of brain-derived A␤ via transport-mediated clearance mechanisms (r...