Aβ ion channels. Prospects for treating Alzheimer's disease with Aβ channel blockers

Abstract

The main pathological features in the Alzheimer's brain are progressive depositions of amyloid protein plaques among nerve cells, and neurofibrillary tangles within the nerve cells. The major components of plaques are Abeta peptides. Numerous reports have provided evidence that Abeta peptides are cytotoxic and may play a role in the pathogenesis of AD. An increasing number of research reports support the concept that the Abeta-membrane interaction event may be followed by the insertion of Abeta into the membrane in a structural configuration which forms an ion channel. This review summarizes experimental procedures which have been designed to test the hypothesis that the interaction of Abeta with a variety of membranes, both artificial and natural, results in the subsequent formation of Abeta ion channels We describe experiments, by ourselves and others, that support the view that Abeta is cytotoxic largely due to the action of Abeta channels in the cell membrane. The interaction of Abeta with the surface of the cell membrane may results in the activation of a chain of processes that, when large enough, become cytotoxic and induce cell death by apoptosis. Remarkably, the blockage of Abeta ion channels at the surface of the cell absolutely prevents the activation of these processes at different intracellular levels, thereby preserving the life of the cells. As a prospect for therapy for Alzheimer's disease, our findings at cellular level may be testable on AD animal models to elucidate the potential role and the magnitude of the contribution of the Abeta channels for induction of the disease.

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

“…More recently, basing our work on an earlier least-energy molecular model of the oligomeric Abeta channel (44 and [supporting information (SI) Fig. S1]), we found that highly selective A␤ channel blockers could be created from polypeptide segments predicted by the model to line the mouth of the A␤ pore (34,(45)(46)(47)(48). Furthermore, these polypeptide inhibitors also proved to be potent inhibitors of A␤ neurotoxicity.…”

“…In fact, previous data of this sort have contributed to the compelling support for the A␤ calcium channel hypothesis for the pathogenesis of Alzheimer's disease (45). However, with the exception of the other blocking compounds modeled after the amino acid sequences forming the mouth of the Abeta pore (34,(45)(46)(47)(48), the other inhibitors, such as Tris and Zn 2ϩ could be considered somewhat on the less potent side of the concentration/efficacy scale. For example, relatively high concentrations of Tris (1-10 mM) are needed both to block Abeta channels (32) and to protect against neurotoxicity (42).…”

Using model membranes for the study of amyloid beta:lipid interactions and neurotoxicity

“…The predominant ones are Ab-40 ( 90%) and Ab-42 ( 10%). Once produced, Ab-peptides exert their damaging effects both extra-and intra-cellularly (Arispe et al, 2007;Nunan and Small, 2000;Stine et al, 2003;Verdile et al, 2004).…”

“…First pioneered by Arispe et al (1993), this mechanism is now commonly referred to as the b-amyloid calcium channel hypothesis after its inception in 1994 (Arispe et al, 1994). Readers are referred to a recent review by the same authors, for an indepth discussion on the Ab ion channel-based neurodegenerative mechanism (Arispe et al, 2007). The ion channels would allow excessive calcium influx into the cell, causing destabilization of cellular ionic homeostasis and inducing cell pathophysiology and neuritic degeneration in amyloid diseases (Lin et al, 2001;Quist et al, 2005).…”

“…Mechanisms for Alzheimer's neurotoxicity through soluble oligomers, and formation of Ab aggregates and fibrils. Amyloid b is implicated in (I) binding to receptors, thus altering signal transduction systems, (II) causing cell membrane damage leading to pore formation and production of free radicals, and (III) altering ion movement through interaction (blocking, for example) with ion channels (Arispe et al, 2007;McLaurin and Chakrabartty, 1996;Quist et al, 2005;Varadarajan et al, 2000).…”