The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease

Abstract

The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is necessary to generate the Aβ peptide, which is implicated in Alzheimer's disease pathology. Studies show that the expression of BACE1 and its protease activity are tightly regulated, but the physiological function of BACE1 remains poorly understood. Recently, numerous axon guidance proteins were identified as potential substrates of BACE1. Here, we examined the consequences of loss of BACE1 function in a well-defined in vivo model system of axon guidance, mouse olfactory sensory neurons (OSNs). The BACE1 protein resides predominantly in proximal segment and the termini of OSN axons, and the expression of BACE1 inversely correlates with odor-evoked neural activity. The precision of targeting of OSN axons is disturbed in both BACE1 null and, surprisingly, in BACE1 heterozygous mice. We propose that BACE1 cleavage of axon guidance proteins is essential to maintain the connectivity of OSNs in vivo.

Spontaneous and sensory-evoked activity in mouse olfactory sensory neurons with defined odorant receptors

“…Additional noncanonical targets of spontaneous activity and/or homeostatic mechanisms that could influence development and maintenance of OSN synapses include retinoic acid receptors (Oztokatli et al 2012) and the ␤-site amyloid precursor protein cleaving enzyme 1 (Cao et al 2012;Rajapaksha et al 2011). …”

The Neural Cell Adhesion Molecules L1 and CHL1 Are Cleaved by BACE1 Protease in Vivo

“…Two APP peptides ending or starting directly from the BACE1 cleavage site were only identified from the control sample but not from the BACE1 inhibitor-treated sample; thus, the light/heavy ratio of APP was infinite (indicated with *). (59,60). We therefore prepared synaptosomal and synaptic membrane fractions from both BACE1 knock-out mice (using wild type mice as control) and wild type mice after acute treatment with compound J (using vesicle-treated mice as control).…”

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

“…Infrapyramidal Bundle Length-We sought to determine whether axon guidance defects were more widespread, beyond OSN axon targeting errors in the olfactory bulb (1,25), in the brains of BACE1 Ϫ/Ϫ mice. We chose to investigate the hippocampal mossy fiber axons that project from dentate gyrus granule cells to CA3 pyramidal neurons, because they are highly plastic and crucial for memory formation.…”

“…Recently, we (1) and other investigators (25) reported that BACE1 Ϫ/Ϫ mice exhibit defects in the guidance of OSN axons to odorant receptor-specific glomeruli in the olfactory bulb. Because OSNs regenerate throughout life and require on-going axon guidance in the adult, we reasoned that BACE1 deficiency might cause axon mis-targeting in other adult axon regenerating and neurogenic systems in BACE1 Ϫ/Ϫ mice.…”

“…Initial reports indicated that BACE1 Ϫ/Ϫ mice were viable, fertile, and devoid of abnormalities. However, upon closer examination, BACE1 Ϫ/Ϫ mice were found to have several subtle phenotypes that involved memory deficits (16 -18), hypomyelination (19,20), reduced survival and growth retardation (21), irregularities in neuronal excitability and electrophysiology (17,21,22), seizure (22,23), reduced dendritic spine density (24), schizophrenia endophenotypes (24), and axon guidance defects (1,25). Although these BACE1 null abnormalities are relatively mild, they are complex neurological phenotypes that raise a concern that BACE1 inhibitors may not be completely free of mechanism-based side effects.…”