Why is the amyloid beta peptide of Alzheimer's disease neurotoxic?
In this article, we support the case that the neurotoxic agent in Alzheimer's disease is a soluble aggregated form of the amyloid beta peptide (Abeta), probably complexed with divalent copper. The structure and chemical properties of the monomeric peptide and its Cu(ii) complex are discussed, as well as what little is known about the oligomeric species. Abeta oligomers are neurotoxic by a variety of mechanisms. They adhere to plasma and intracellular membranes and cause lesions by a combination of radical-initiated lipid peroxidation and formation of ion-permeable pores. In endothelial cells this damage leads to loss of integrity of the blood-brain barrier and loss of blood flow to the brain. At synapses, the oligomers close neuronal insulin receptors, mirroring the effects of Type II diabetes. In intracellular membranes, the most damaging effect is loss of calcium homeostasis. The oligomers also bind to a variety of substances, mostly with deleterious effects. Binding to cholesterol is accompanied by its oxidation to products that are themselves neurotoxic. Possibly most damaging is the binding to tau, and to several kinases, that results in the hyperphosphorylation of the tau and abrogation of its microtubule-supporting role in maintaining axon structure, leading to diseased synapses and ultimately the death of neurons. Several strategies are presented and discussed for the development of compounds that prevent the oligomerization of Abeta into the neurotoxic species.
Rauk
Arvi
A
Department of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada.
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D006801:Humans; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D016062:Porosity; D011485:Protein Binding
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments