Issue 10, 2008

Why is the amyloid beta peptide of Alzheimer's disease neurotoxic?

Abstract

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 (Aβ), 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. Aβ 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 Aβ into the neurotoxic species.

Graphical abstract: Why is the amyloid beta peptide of Alzheimer's disease neurotoxic?

Article information

Article type
Frontier
Submitted
03 Dec 2007
Accepted
14 Jan 2008
First published
12 Feb 2008

Dalton Trans., 2008, 1273-1282

Why is the amyloid beta peptide of Alzheimer's disease neurotoxic?

A. Rauk, Dalton Trans., 2008, 1273 DOI: 10.1039/B718601K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements