Amyloid-β oligomers: their production, toxicity and therapeutic inhibition

Abstract

Despite extensive genetic and animal modelling data that support a central role for the amyloid beta-protein (A beta) in the genesis of Alzheimer's disease, the specific form(s) of A beta which causes injury to neurons in vivo has not been identified. In the present study, we examine the importance of soluble, pre-fibrillar assemblies of A beta as mediators of neurotoxicity. Specifically, we review the role of cell-derived SDS-stable oligomers, their blocking of hippocampal long-term potentiation in vivo and the finding that this blocking can be prevented by prior treatment of oligomer-producing cells with gamma-secretase inhibitors.

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

“…In addition, we exclusively used soluble Aβ derived from a CHO cell line (7PA2) that expresses APP carrying the V717F mutation. This cell line secretes high levels of monomeric and small oligomeric Aβ, without larger insoluble aggregates (Walsh, et al, 2002b). Our results indicate that low levels of soluble Aβ rapidly alter dendritic spine morphology and uncouple dendritic spines from their nerve terminals.…”

“…These cells were previously shown to secrete all natural derivatives of APP metabolism, including monomers, SDS-stable low-n oligomers, and soluble APP, but no detectable Aβ fibrils (Podlisny, et al, 1995;Walsh, et al, 2002b). Exposure of brain tissue to low concentrations of this medium inhibited the induction of LTP in vivo (Walsh, et al, 2002a) and in hippocampal slices (Townsend, et al, 2006;Wang, et al, 2002), and induced cognitive deficits in vivo (Cleary, et al, 2005).…”

“…More recently, new evidence suggests that soluble forms of Aβ, rather than the fibrillar forms visible as amyloid plaques, hold the key to understanding AD brain pathology (Small and Cappai, 2006;Walsh, et al, 2002b). To date, many studies of molecular mechanisms underlying AD have focused on neuronal cell death as an endpoint, because extensive neuronal cell loss occurs as AD progresses.…”

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

“…A considerable body of experimental evidence suggests that the Alzheimer peptide (Ab) under certain conditions exists in the form of soluble spherical oligomers, which are often described as "protein micelles" or "Ab-derived diffusible ligands (ADDLs)" (for recent reviews see [59,60]). Based on this evidence, Kayed et al [61] generated a molecular mimic in which the C-terminus of the Ab 1-40 peptide was covalently linked to gold particles.…”

Impact of amyloid imaging on drug development in Alzheimer's disease

“…In summary, the evidence that oligomeric Aβ42 is the most toxic species of Aβ is convincing. Studies strongly support the following: 1) all else being equal, enriched oligomeric preparations of Aβ42 appear to be the most toxic species [38,39]; 2) oligomeric species of Aβ42 can inhibit long term potentiation (LTP) and lead to synaptic dysfunction [48,49]; 3) memory loss occurs prior to extensive deposition of fibrillar Aβ42 in transgenic mice and can be reversed by targeting soluble species of Aβ42 [50,51,52,53]; and 4) oligomeric Aβ42 species exist in AD brain [54]. However, it is important to appreciate that the removal or reduction of the soluble, toxic oligomeric forms of Aβ42 from brain parenchyma will require the concomitant reduction and removal of the insoluble (fibrillar) Aβ42 pool as well.…”