We found that the amyloid  peptide A(1-42) is capable of interacting with membrane and forming heterogeneous ion channels in the absence of any added Cu 2ϩ or biological redox agents that have been reported to mediate A(1-42) toxicity. binds to the histidine residues located at the mouth of the channel. It is proposed that the Cu 2ϩ -binding site of the A(1-42)-formed channels is modulated with Cu 2ϩ in a similar way to those of channels formed with the prion protein fragment PrP(106-126), suggesting a possible common mechanism for Cu 2ϩ modulation of A and PrP channel proteins linked to neurodegenerative diseases. neurodegenerative diseases; transitional metals; ion channel pathologies; membrane injuries; calcium homeostasis ALZHEIMER'S DISEASE (AD) is a neurodegenerative disorder that affects the cognitive function of the brain. Pathological changes in AD are characterized by the formation of amyloid plaques and neurofibrillary tangles as well as extensive neuronal loss. The plaques, which accumulate extracellularly in the brain, are composed of aggregates and cause direct neurotoxic effects and/or increase neuronal vulnerability to excitotoxic insults. The major components of the extracellular neurofibrillar bundles are polymerized amyloid  (A) peptides A(1-40), A(1-42), and A(1-43). It has been shown that A familial AD-linked mutations of the amyloid protein precursors presenilin-1 and presenilin-2 increase the concentration of A(1-42) (53), which has been shown to be toxic in primary neuronal culture at micromolar concentrations (56). The major mechanisms proposed for A-induced cytotoxicity involve the loss of Ca 2ϩ homeostasis (see Refs. 46 and 47) and the generation of reactive oxygen species (see Refs. 9,11,12,and 25). The changes in Ca 2ϩ homeostasis could be the result of 1) alterations in endogenous ion transport systems and 2) formation of heterogeneous ion channels (see Refs. 32,33,and 35). Several laboratories have found that A(1-40) and other fragments of amyloid precursor protein that contain A also possess the ability to form ion channels in both artificial and biological membranes. Electrophysiological studies have shown that A fragments, e.g., A(25-35), A(1-40), and A(1-42), elicit cation-selective currents when reconstituted into lipid bilayers (1-4, 23, 24, 30, 35, 37, 41, 55) and in the plasma membrane of neurons (28,29,48) as well as in Xenopus oocytes (21). A(1-42) and A(1-40) increase Ca 2ϩ uptake in liposomes in a dose-dependent manner (38, 49), and soluble As induce Ca 2ϩ influx in neurons and nonneuronal cells (10,50,51,57).In addition to the A being linked to AD, a role for transition metals has also been recognized. Cu 2ϩ and Zn 2ϩ have been implicated in AD (11,12,42), Parkinson's disease (54), prion protein (PrP) (26), and immunoglobulin light chain amyloidosis (17). The mechanisms underlying the interaction between A and these metals may mediate their role in neurotoxicity. There is also evidence to show that A, and also PrP, binds Cu 2ϩ (5, 6) to a si...