This report demonstrates that passive immunotherapy with amyloid-β(Aβ)-targeting antibodies in Alzheimer transgenic mice was both ineffective in treating neuronal dysfunction, and actually worsened it. Administration of two different monoclonal antibodies resulted in significantly increased numbers of pathologically hyperactive neurons and promoted, in some cases, abnormal synchrony of cortical activity. The findings indicate that the previously reported beneficial effects of antibody treatment on neuronal structure, including recovery of neuritic dystrophy or prevention of synaptophysin loss, are not sufficient for the repair of neuronal dysfunction.
The authors concluded that the aggravation of neuronal hyperactivity is directly related to binding of the antibodies to Aβ rather than to some non-Aβ–related properties of the antibodies. Although inflammatory processes did not seem to have a prominent role under their experimental conditions, they could not exclude the possibility that inflammatory effects of passive immunotherapy could contribute to increased neuronal hyperactivity in transgenic animals. The pro-excitatory effect was not observed in wild-type animals; thus, even if the increased hyperactivity involves inflammation, it must be Aβ dependent. Together, their results suggest a cellular mechanism that, in combination with other factors, may be the reason for the failure of anti-Aβ immunotherapies in repairing cognitive deficits.

Busche MA, Grienberger C, Keskin AD, Song B, Neumann U, Staufenbiel M, Förstl H, Konnerth A: Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models. Nature Neuroscience [Epub ahead of print, Nov. 9, 2015; doi: 10.1038/nn.4163].

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