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J Exp Med. 2018 Mar 5;215(3):927-940. doi: 10.1084/jem.20171831. Epub 2018 Feb 14.

BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions.

Author information

1
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH hux@ccf.org.
2
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
3
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH Riyan@uchc.edu.

Abstract

BACE1 initiates the generation of the β-amyloid peptide, which likely causes Alzheimer's disease (AD) when accumulated abnormally. BACE1 inhibitory drugs are currently being developed to treat AD patients. To mimic BACE1 inhibition in adults, we generated BACE1 conditional knockout (BACE1fl/fl) mice and bred BACE1fl/fl mice with ubiquitin-CreER mice to induce deletion of BACE1 after passing early developmental stages. Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model (5xFAD) was capable of completely reversing amyloid deposition. This reversal in amyloid deposition also resulted in significant improvement in gliosis and neuritic dystrophy. Moreover, synaptic functions, as determined by long-term potentiation and contextual fear conditioning experiments, were significantly improved, correlating with the reversal of amyloid plaques. Our results demonstrate that sustained and increasing BACE1 inhibition in adults can reverse amyloid deposition in an AD mouse model, and this observation will help to provide guidance for the proper use of BACE1 inhibitors in human patients.

PMID:
29444819
PMCID:
PMC5839766
DOI:
10.1084/jem.20171831
[Indexed for MEDLINE]
Free PMC Article

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