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

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 gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after 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.

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

“…To determine the contribution of GABAergic neurons to the initial deposition of Aβ plaques, we blocked Aβ production specifically in GABAergic neurons by conditional knock-out of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) [18] under the control of Glutamate Decarboxylase 2 (Gad2-Cre) in App NL-G-F/NL-G-F mice. As validation that Gad2-Cre targets the appropriate cells with high APP-expression, we observed loss of APP immunoreactivity in GABA B R1-positive interneurons in Aplp2 −/− App flox/flox ; Gad2-Cre mice compared to Gad2-Cre control mice (Additional file 4: Figure S4).…”

“…All animal experiments were conducted according to the KU Leuven ethical guidelines and approved by the KU Leuven Committee on Animal Care. Generation of the App NL-G-F mice, Bace1 flox/flox , App KO, and Aplp2 −/− App flox/flox mice were described previously [2,15,18,23]. GAD2Cre mice were obtained from Jackson Laboratory (Jax 010802).…”

Opposite Roles of δ- and μ-Opioid Receptors in BACE1 Regulation and Alzheimer’s Injury

“…Germline BACE1 knockout mice have been reported to exhibit reduced survival rate, hypomyelination, seizures, and memory deficits (Laird et al, 2005;Hitt et al, 2010;Hu et al, 2010;Barao et al, 2016). Conditional BACE1 knockout mice showed disrupted organization of axonal pathway in the hippocampus, an important region for learning and memory (Ou-Yang et al, 2018). These results indicate the importance of proper expression and function of BACE1 in the survival and function of nerve cells.…”

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects

“…Whether this finding is the result of an off-target liability, such as BACE2 inhibition; an on-target, off-mechanism effect on a non-A␤ substrate such as neuregulin or seizure protein 6; or an on-target, on-mechanism effect such as interference with the physiologic role of A␤ is unknown. In addition to targeting patients who are earlier in the AD spectrum, future trials of BACE1 inhibitors may need to test doses that yield lower levels of inhibition in order to preserve normal synaptic functioning [32,33].…”