Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss

Abstract

A molecular basis for memory failure in Alzheimer's disease (AD) has been recently hypothesized, in which a significant role is attributed to small, soluble oligomers of amyloid ␤-peptide (A␤). A␤ oligomeric ligands (also known as ADDLs) are known to be potent inhibitors of hippocampal long-term potentiation, which is a paradigm for synaptic plasticity, and have been linked to synapse loss and reversible memory failure in transgenic mouse AD models. If such oligomers were to build up in human brain, their neurological impact could provide the missing link that accounts for the poor correlation between AD dementia and amyloid plaques. This article, using antibodies raised against synthetic A␤ oligomers, verifies the predicted accumulation of soluble oligomers in AD frontal cortex. Oligomers in AD reach levels up to 70-fold over control brains. Brain-derived and synthetic oligomers show structural equivalence with respect to mass, isoelectric point, and recognition by conformation-sensitive antibodies. Both oligomers, moreover, exhibit the same striking patterns of attachment to cultured hippocampal neurons, binding on dendrite surfaces in small clusters with ligand-like specificity. Binding assays using solubilized membranes show oligomers to be high-affinity ligands for a small number of nonabundant proteins. Current results confirm the prediction that soluble oligomeric A␤ ligands are intrinsic to AD pathology, and validate their use in new approaches to therapeutic AD drugs and vaccines.

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

“…The availability of antibodies specific to small soluble aggregates (antibody 6 in Fig. 1) therefore enables the role of such species in protein aggregation diseases to be probed in detail [61,77,78]. Remarkably, the oligomer-specific generic antibodies have been reported to be capable of protecting cultured cells against the toxicity of aggregates derived from a variety of proteins [61].…”

“…By using antibodies specific to small soluble aggregates, the presence of such aggregates has been identified in brain sections from transgenic mice models and from sufferers of Alzheimer's disease [61,77,78]. The ratio of the amount of this type of aggregate in AD-brains versus control brains has been estimated to be up to 70:1 [78].…”

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

“…Thus, it may be reasonable to speculate that NSAIDs could prevent the development of AD, not only through suppressing chronic neuroinflammation and reducing the amount of soluble Aß(1-42) peptide levels, but also through directly inhibiting the deposition of fAß in the brain. In relation to the latter scenario, it may be essential to evaluate the effect of NSAIDs on the Aß oligomer formation in a future study, because the Aß oligomer has been reported to be the most neurotoxic form of all the Aß aggregates (Gong et al, 2003). Yang et al (2005) recently reported that curcumin prevented Aß42 oligomer formation and toxicity between 0.1 and 1.0 µM, which is consistent with our EC 50 values of curcumin for the anti-amyloidogenic and fibril-destabilizing activity (Ono et al, 2004b).…”

Development and Expression of Amyloid‐β Peptide 42 in Retinal Ganglion Cells in Rats

“…Recent data indicates that neuronal injuries and death have been correlated with the status of Ab-42 (Sponne et al, 2004;Kriem et al, 2005). Despite there are studies suggesting the role of soluble Ab-42 in promoting the growth of neurapophysis and enhancing neuron survival in a short time, other researches has shown that soluble Ab-42 oligomers may be the proximate effectors of AD and that Ab-42 in soluble oligomeric status can induce neuronal death (Gong et al, 2003;Kim et al, 2003;Florent et al, 2006). The neurotoxic molecular mechanisms of soluble Ab-42 oligomers remain unknown.…”