Innate immune signaling in the olfactory epithelium reduces odorant receptor levels: modeling transient smell loss in COVID-19 patients.

Post-infectious anosmias typically follow death of olfactory sensory neurons (OSNs) with a months-long recovery phase associated with parosmias. While profound anosmia is the leading symptom associated with COVID-19 infection, many patients regain olfactory function within days to weeks without distortions. Here, we demonstrate that sterile induction of anti-viral type I interferon signaling in the mouse olfactory epithelium is associated with diminished odor discrimination and reduced odor-evoked local field potentials. RNA levels of all class I, class II, and TAAR odorant receptors are markedly reduced in OSNs in a non-cell autonomous manner. We find that people infected with COVID-19 rate odors with lower intensities and have odor discrimination deficits relative to people that tested negative for COVID-19. Taken together, we propose that inflammatory-mediated loss of odorant receptor expression with preserved circuit integrity accounts for the profound anosmia and rapid recovery of olfactory function without parosmias caused by COVID-19.

Aß alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo.

The amyloid beta peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) before the onset of plaques. Expression of human APPsw exclusively in olfactory sensory neurons also perturbs connectivity with associated reductions in odour-evoked gene expression and olfactory acuity. By contrast, olfactory sensory neuron axons project correctly in mice overexpressing wild-type human amyloid precursor protein throughout the brain and in mice overexpressing M671V human APP, a missense mutation that reduces amyloid beta production, exclusively in olfactory sensory neurons. Furthermore, expression of Aß40 or Aß42 solely in the olfactory epithelium disrupts the olfactory sensory neuron axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human amyloid beta.

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

The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is necessary to generate the Aß 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.