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

Abstract

Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A␤). We have hypothesized that the intrinsic A␤ calcium channel activity of the oligomeric A␤ polymer may be responsible for the neurotoxic properties of A␤, and that A␤ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A␤ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A␤ channel and protect neurons from A␤ toxicity. Both block the A␤ channel with similar potency (Ϸ500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.brain ͉ neurodegeneration ͉ rational drug design ͉ drug ͉ toxicity A lzheimer's disease (AD) is a chronic neurodegenerative disease characterized behaviorally by progressive memory loss, and neuronal degeneration in the cerebral cortex, hippocampus, and elsewhere (1, 2). The neuropathology of AD is characterized by amyloid plaques and neuro-fibrillary tangles. The amyloid plaque material has been found to be composed principally of a 40Ϫ42-residue peptide, called amyloid ␤-peptide, or ''A␤'' (3). Both forms of A␤40/42 have been found to be kill neurons and certain other cells in culture. Altogether, these findings have provided strong support for the hypothesis that AD is due to neurotoxic effects of A␤ on susceptible neurons (4-10).The mechanism of A␤ neurotoxicity has been pursued for decades in hopes of translating such knowledge into a pharmaceutical therapy for AD. Cholinesterase inhibitors were the first generation of such candidate therapeutics (11-15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16-23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26). Yet another alternative has been to reduce the levels of A␤ in the brain by inhibiting the proteolytic enzymes associated with trimming APP into A␤ 40 or 42 (27-31).An entirely different approach to the mechanism of A␤ neurotoxicity has been developed following the observation that oligomers of A␤ peptides themselves formed calcium conducting channels in bilayer membranes in vitro (32)(33)(34)(35), and in intact neurons (36). The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38-42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be respo...

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

“…All rights reserved Several investigators have shown that such species can be extracted from affected brain tissue using saline buffers without detergents [12,13]. Oligomer cytotoxicity appears to result from the aberrant interactions of such species with the lipid bilayers, disrupting cell membranes and impairing their ability to maintain cellular homeostasis [14][15][16][17][18]. Several studies support the notion that membrane disruption induced by A␤ allows the entry of small molecules and ions, mainly free Ca 2+ ions [19][20][21][22].…”

Amyloid beta: structure, biology and structure-based therapeutic development

“…Aβ oligomers can form calcium channels in membranes. Calcium conductance through these channels can be blocked by compounds MRS2481 and MRS2485, which destabilize the β-sheet structure and decrease Aβ-promoted neuronal toxicity [322] . Bexarotene might serve as another class of anti-Alzheimer compounds by efficiently preventing the cholesterol-dependent increase in calcium fluxes promoted by Aβ in neural cells [323] .…”

Chiral Metallohelical Complexes Enantioselectively Target Amyloid β for Treating Alzheimer’s Disease

“…Perturbation of calcium homeostasis may also contribute to a self-amplifying cascade of free radical-and Ca 2+ -mediated degenerative processes which involved in the neurodegenerative phenotype of Alzheimer's disease. [64][65][66] Effective blocking Aβ formed calcium channel can be critical for protection of the cells from Aβ cytotoxicity. To test the hypothesis that these metal complexes were interfering with Aβ-dependent intracellular calcium change, we used the cell-permeant calcium-sensitive dye Fluo-3 AM to measure intracellular calcium levels in treated cells.…”