An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease

Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-β (Aβ) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble Aβ aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dys...

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Bibliographic Details
Published in:Neurobiology of Disease
Main Authors: Anna Lord, Astrid Gumucio, Hillevi Englund, Dag Sehlin, Valentina Screpanti Sundquist, Linda Söderberg, Christer Möller, Pär Gellerfors, Lars Lannfelt, Frida Ekholm Pettersson, Lars N.G. Nilsson
Format: Article in Journal/Newspaper
Language:English
Published: Elsevier 2009
Subjects:
Alzheimer's disease
Immunotherapy
Monoclonal antibody
Soluble amyloid-β
Intraneuronal
Transgenic mice
Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Arctic
Online Access:https://doi.org/10.1016/j.nbd.2009.08.007
https://doaj.org/article/8d9b05a83ab94d769640cf77ac14dd39
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Summary:Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-β (Aβ) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble Aβ aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dysfunction and dementia. Here we explored selective targeting of large soluble aggregates, Aβ protofibrils, as a new immunotherapeutic strategy. The highly protofibril-selective monoclonal antibody mAb158 inhibited in vitro fibril formation and protected cells from Aβ protofibril-induced toxicity. When the mAb158 antibody was administered for 4 months to plaque-bearing transgenic mice with both the Arctic and Swedish mutations (tg-ArcSwe), Aβ protofibril levels were lowered while measures of insoluble Aβ were unaffected. In contrast, when treatment began before the appearance of senile plaques, amyloid deposition was prevented and Aβ protofibril levels diminished. Therapeutic intervention with mAb158 was however not proven functionally beneficial, since place learning depended neither on treatment nor transgenicity. Our findings suggest that Aβ protofibrils can be selectively cleared with immunotherapy in an animal model that display highly insoluble Aβ deposits, similar to those of Alzheimer's disease brain.

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