Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model

Abstract

In Alzheimer disease, increased β-secretase (BACE1) activity has been associated with neurodegeneration and accumulation of amyloid precursor protein (APP) products. Thus, inactivation of BACE1 could be important in the treatment of Alzheimer disease. In this study, we found that lowering BACE1 levels using lentiviral vectors expressing siRNAs targeting BACE1 reduced amyloid production and the neurodegenerative and behavioral deficits in APP transgenic mice, a model of Alzheimer disease. Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage of APP and neurodegeneration in vivo and indicate that this approach could have potential therapeutic value for treatment of Alzheimer disease.

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Figure 1: Construct design and in vitro testing of lenti-siRNA constructs.
Figure 2: Characterization of the effects of lenti-siBACE1-6 expression in the brains of APP transgenic mice.
Figure 3: Immunolabeling patterns of BACE1 expression and the lenti-siRNA distribution.
Figure 4: Effects of the lenti-siBACE1-6 treatment on APP processing and amyloid deposition.
Figure 5: Effects of lenti-siBACE1-6 on neuronal integrity.
Figure 6: Behavioral analysis of transgenic mice treated with lenti-siBACE1-6 in the Morris water maze.

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Acknowledgements

This work was supported by US National Institutes of Health grants AG5131, AG10435, AG18440 and AG08514 to F.H.G. R.A.M. was supported in part by fund from the Canadian Institutes of Health Research.

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Correspondence to Inder M Verma or Eliezer Masliah.

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Singer, O., Marr, R., Rockenstein, E. et al. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 8, 1343–1349 (2005). https://doi.org/10.1038/nn1531

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