Specific targeting of a highly toxic subpopulation of Aβ42 oligomers for the treatment of Alzheimer’s disease

Abstract

AbstractBackgroundNon‐clinical data on the etiology of Alzheimer’s disease (AD) suggest that only a very small fraction of soluble oligomeric Aβ42 carries most of the neurotoxic potency. But the study of Aβ42 soluble species has been hampered by their intrinsic heterogeneous and dynamic nature. A unique oligomer‐stabilizing technology, AβCC, enables the development of therapies that target these specifically. We here demonstrate the development such immunotherapies that exhibit unique Aβ oligomer targeting activity which translates into high efficacy in non‐clinical models of the disease.MethodStable synthetic Aβ42CC peptide oligomer derivatives were used as antigens in an active vaccine and were used to develop a murine monoclonal antibody, ALZ‐201. Efficacy was evaluated on brain extracts from AD patients and controls. These brain extracts were immunodepleted with ALZ‐201 and control antibodies. Toxicity assays were then performed in primary mouse neuronal cultures using an automated cell imaging platform. In addition, acute neurotoxicity effects on memory formation in zebrafish were assessed following intracranial injections of the brain extracts.ResultThe AβCC oligomers were able to generate truly oligomer‐specific antibodies. AD extracts exhibited higher levels of toxicity in contrast to non‐AD extracts in both cells assays and in zebrafish. This toxicity was highly dependent on Aβ, shown by immunodepletion with 4G8. Comparable toxicity was observed for brain extracts immunodepleted with ALZ‐201 as for extracts immunodepleted with 4G8. Interestingly, the soluble Aβ42 species captured by ALZ‐201 were below the limit of detection with the standard biochemical techniques used for analysis.ConclusionThe data support the hypothesis that a specific subtype of Aβ42 oligomers has large neurotoxic effects in the central nervous system that can affect synaptic plasticity, learning and memory. These oligomers are present in very small amounts and, due to the inaccessible environment, are not likely to be targeted with non‐specific anti‐Aβ immunotherapies. In contrast, targeting them specifically may serve as effective future treatments.