Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice

Ming Hsuan Ou-Yang, Jonathan Kurz, Toshihiro Nomura, Jelena Popovic, Tharinda W. Rajapaksha, Hongxin Dong, Anis Contractor, Dane M. Chetkovich, Warren G. Tourtellotte, Robert J Vassar*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

b-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the b-secretase enzyme that initiates production of the toxic amyloid-b peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear. Germline BACE1 knockout mice have multiple neurological phenotypes, although these could arise from BACE1 deficiency during development. To address this question, we report that tamoxifen-inducible conditional BACE1 knockout mice in which the Bace1 gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after Bace1 gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced BACE1-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that BACE1 inhibition in the adult mouse brain may avoid phenotypes associated with BACE1 deficiency during embryonic and postnatal development, they also suggest that BACE1 inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.

Original languageEnglish (US)
Article numbereaao5620
JournalScience translational medicine
Volume10
Issue number459
DOIs
StatePublished - Sep 19 2018

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Knockout Mice
Hippocampus
Phenotype
Alzheimer Disease
Brain
Hippocampal Mossy Fibers
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Poisons
Neurogenesis
Dentate Gyrus
Gene Deletion
Enzymes
Tamoxifen
Amyloid
Cell Adhesion
Pharmaceutical Preparations
Embryonic Development
Clinical Trials
Learning

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ou-Yang, Ming Hsuan ; Kurz, Jonathan ; Nomura, Toshihiro ; Popovic, Jelena ; Rajapaksha, Tharinda W. ; Dong, Hongxin ; Contractor, Anis ; Chetkovich, Dane M. ; Tourtellotte, Warren G. ; Vassar, Robert J. / Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. In: Science translational medicine. 2018 ; Vol. 10, No. 459.
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Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. / Ou-Yang, Ming Hsuan; Kurz, Jonathan; Nomura, Toshihiro; Popovic, Jelena; Rajapaksha, Tharinda W.; Dong, Hongxin; Contractor, Anis; Chetkovich, Dane M.; Tourtellotte, Warren G.; Vassar, Robert J.

In: Science translational medicine, Vol. 10, No. 459, eaao5620, 19.09.2018.

Research output: Contribution to journalArticle

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AU - Ou-Yang, Ming Hsuan

AU - Kurz, Jonathan

AU - Nomura, Toshihiro

AU - Popovic, Jelena

AU - Rajapaksha, Tharinda W.

AU - Dong, Hongxin

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AU - Tourtellotte, Warren G.

AU - Vassar, Robert J

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