RESUMEN
Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use respiratory epithelial cells as an entry point for infection. Within the nasal cavity, the olfactory epithelium (OE) is particularly sensitive to infections which may lead to olfactory dysfunction. In patients suffering from coronavirus disease 2019, deficits in olfaction have been characterized as a distinctive symptom. Here, we used the K18hACE2 mice to study the spread of SARS-CoV-2 infection and inflammation in the olfactory system (OS) after 7â d of infection. In the OE, we found that SARS-CoV-2 selectively targeted the supporting/sustentacular cells (SCs) and macrophages from the lamina propria. In the brain, SARS-CoV-2 infected some microglial cells in the olfactory bulb (OB), and there was a widespread infection of projection neurons in the OB, piriform cortex (PC), and tubular striatum (TuS). Inflammation, indicated by both elevated numbers and morphologically activated IBA1+ cells (monocyte/macrophage lineages), was preferentially increased in the OE septum, while it was homogeneously distributed throughout the layers of the OB, PC, and TuS. Myelinated OS axonal tracts, the lateral olfactory tract, and the anterior commissure, exhibited decreased levels of 2',3'-cyclic-nucleotide 3'-phosphodiesterase, indicative of myelin defects. Collectively, our work supports the hypothesis that SARS-CoV-2 infected SC and macrophages in the OE and, centrally, microglia and subpopulations of OS neurons. The observed inflammation throughout the OS areas and central myelin defects may account for the long-lasting olfactory deficit.
Asunto(s)
COVID-19 , Vaina de Mielina , Bulbo Olfatorio , Mucosa Olfatoria , SARS-CoV-2 , Animales , COVID-19/patología , COVID-19/complicaciones , Ratones , Mucosa Olfatoria/patología , Mucosa Olfatoria/virología , Bulbo Olfatorio/patología , Bulbo Olfatorio/virología , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Microglía/patología , Microglía/metabolismo , Microglía/virología , Ratones Transgénicos , Enzima Convertidora de Angiotensina 2/metabolismo , Trastornos del Olfato/patología , Trastornos del Olfato/virología , Modelos Animales de Enfermedad , Masculino , Inflamación/patología , Inflamación/virología , Macrófagos/patología , FemeninoRESUMEN
Parkinson's disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6-7 and 12-14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12-14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12-14 months. Our data suggest that (1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD; (2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology; (3) α-syn pathology is restricted to projection neurons in the olfactory pathway; (4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and (5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.SIGNIFICANCE STATEMENT Olfactory dysfunction is a characteristic symptom of Parkinson's disease (PD). Using the human A30P mutant α-synuclein (α-syn)-expressing mouse model, we demonstrated the appearance of olfactory deficits at late stages of the disease, which was accompanied by the accumulation of α-syn pathology in projection neurons (PNs) of the olfactory system. This dysfunction included a reduction in olfactory bulb (OB) neurogenesis as well as changes in synaptic vesicular transport affecting synaptic function, both of which are likely contributing to olfactory behavioral deficits.