Research ArticleAlzheimer’s Disease

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

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Science Translational Medicine  19 Sep 2018:
Vol. 10, Issue 459, eaao5620
DOI: 10.1126/scitranslmed.aao5620

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Getting back to BACEics

Drugs that block the β-secretase BACE1 are in clinical trials for Alzheimer’s disease. However, their safety is unclear because mice with germline loss of BACE1 exhibit neurological phenotypes, although these could arise from BACE1 deficiency during development. Ou-Yang et al. now have generated conditional BACE1 knockout mice, in which mice underwent development with BACE1 present, and then, the Bace1 gene was ablated in the mature adult animal. Although these adult conditional BACE1 knockout mice largely lacked the phenotypes observed in germline knockout animals, they did exhibit a Bace1-null phenotype involving disorganization of an axonal pathway in the hippocampus, a brain region critical for memory. This suggests that BACE1 inhibitor drugs for treating Alzheimer’s disease could potentially disturb hippocampal axonal pathways.

Abstract

β-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the β-secretase enzyme that initiates production of the toxic amyloid-β 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.

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