RESUMO
Rationale: Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson's disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. Methods: We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and in vitro experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Results: Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. Conclusions: Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders.
Assuntos
Ventrículos Laterais , Camundongos Knockout , Células-Tronco Neurais , Neurogênese , Doença de Parkinson , Proteínas de Ligação a RNA , Receptor Notch1 , Transdução de Sinais , Animais , Masculino , Camundongos , Proliferação de Células , Modelos Animais de Doenças , Ventrículos Laterais/metabolismo , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Transtornos do Olfato/metabolismo , Transtornos do Olfato/genética , Transtornos do Olfato/fisiopatologia , Bulbo Olfatório/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Receptor Notch1/metabolismo , Receptor Notch1/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain's regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.
Assuntos
Tubérculo Olfatório , Peptídeos Opioides , Qualidade de Vida , Olfato , Humanos , Animais , Olfato/fisiologia , Peptídeos Opioides/metabolismo , Peptídeos Opioides/fisiologia , Tubérculo Olfatório/fisiologia , Tubérculo Olfatório/metabolismo , Transtornos do Olfato/fisiopatologia , Transtornos do Olfato/metabolismoRESUMO
Ionic microenvironment of the nasal secretions especially calcium ions play essential role in the olfactory transmission. However, there is a critical need to determine the free calcium levels in healthy people's nasal secretions in contrast to those of patients with olfactory impairment. A selective spectrofluorometric method was created to quantify nasal calcium levels utilizing its quenching ability to the fluorescence of the functionalized carbon quantum dots. The surface of carbon quantum dots was functionalized with calcium ionophore A23187 and ion association complex, calcium phosphotungstate, to improve the selectively to quantify calcium ions. The functionalized carbon quantum dots exhibited a concentration-dependent fluorescence quenching upon interaction with calcium ions. Different factors influencing the quenching process were done to provide efficient analytical process. The new method, demonstrated accurate calcium determination over the concentration range of 200-4000 ng/mL. The suggested technique was used to measure the calcium in the nasal secretions of both healthy people and patients with olfactory impairment. The findings revealed significantly higher calcium levels in the patient with olfactory dysfunction (healthy vs. patient; 735 ± 20 ng/mL vs. 2987 ± 37 ng/mL, p < 0.05).
Assuntos
Cálcio , Espectrometria de Fluorescência , Humanos , Cálcio/análise , Cálcio/metabolismo , Espectrometria de Fluorescência/métodos , Pontos Quânticos/química , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/metabolismo , Mucosa Nasal/metabolismo , Mucosa Nasal/química , Masculino , Adulto , Olfato , FemininoRESUMO
BACKGROUND: Immune-inflammatory response is a key element in the occurrence and development of olfactory dysfunction (OD) in patients with allergic rhinitis (AR). As one of the core factors in immune-inflammatory responses, interleukin (IL)-6 is closely related to the pathogenesis of allergic diseases. It may also play an important role in OD induced by diseases, such as Sjögren's syndrome and coronavirus disease 2019. However, there is no study has reported its role in OD in AR. Thus, this study aimed to investigate the role of IL-6 in AR-related OD, in an attempt to discover a new target for the prevention and treatment of OD in patients with AR. METHODS: Differential expression analysis was performed using the public datasets GSE52804 and GSE140454 for AR, and differentially expressed genes (DEGs) were obtained by obtaining the intersection points between these two datasets. IL-6, a common differential factor, was obtained by intersecting the DEGs with the General Olfactory Sensitivity Database (GOSdb) again. A model of AR mice with OD was developed by sensitizing with ovalbumin (OVA) to verify the reliability of IL-6 as a key factor of OD in AR and explore the potential mechanisms. Furthermore, a supernatant and microglia co-culture model of nasal mucosa epithelial cells stimulated by the allergen house dust mite extract Derp1 was established to identify the cellular and molecular mechanisms of IL-6-mediated OD in AR. RESULTS: The level of IL-6 in the nasal mucosa and olfactory bulb of AR mice with OD significantly increased and showed a positive correlation with the expression of olfactory bulb microglia marker Iba-1 and the severity of OD. In-vitro experiments showed that the level of IL-6 significantly increased in the supernatant after the nasal mucosa epithelial cells were stimulated by Derp1, along with significantly decreased barrier function of the nasal mucosa. The expression levels of neuroinflammatory markers IL-1ß and INOS increased after a conditioned culture of microglia with the supernatant including IL-6. Then knockdown (KD) of IL-6R by small interfering RNA (siRNA), the expression of IL-1ß and INOS significantly diminished. CONCLUSION: IL-6 plays a key role in the occurrence and development of OD in AR, which may be related to its effect on olfactory bulb microglia-mediated neuroinflammation.
Assuntos
Modelos Animais de Doenças , Interleucina-6 , Transtornos do Olfato , Rinite Alérgica , Animais , Camundongos , Interleucina-6/metabolismo , Microglia/metabolismo , Transtornos do Olfato/metabolismo , Bulbo Olfatório/metabolismo , Ovalbumina , Rinite Alérgica/metabolismo , Masculino , Camundongos Endogâmicos C57BLRESUMO
Olfactory dysfunction (OD) is a highly prevalent symptom and an early sign of neurodegenerative diseases in humans. However, the roles of peripheral olfactory system in disease progression and the mechanisms behind neurodegeneration remain to be studied. Olfactory epithelium (OE) organoid is an ideal model to study pathophysiology in vitro, yet the reliance on 3D culture condition limits continual in situ monitoring of organoid development. Here, we combined impedance biosensors and live imaging for real-time spatiotemporal analysis of OE organoids morphological and physiological features during Alzheimer's disease (AD) progression. The impedance measurements showed that organoids generated from basal stem cells of APP/PS1 transgenic mice had lower proliferation rate than that from wild-type mice. In concert with the biosensor measurements, live imaging enabled to visualize the spatial and temporal dynamics of organoid morphology. Abnormal protein aggregation and accumulation, including amyloid plaques and neurofibrillary tangles, was found in AD organoids and increased as disease progressed. This multimodal in situ bioelectrical measurement and imaging provide a new platform for investigating onset mechanisms of OD, which would shed new light on early diagnosis and treatment of neurodegenerative disease.
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Doença de Alzheimer , Técnicas Biossensoriais , Doenças Neurodegenerativas , Transtornos do Olfato , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Células-Tronco/metabolismo , Organoides/metabolismo , Transtornos do Olfato/metabolismo , Peptídeos beta-Amiloides/metabolismoRESUMO
Smell detection depends on nasal airflow, which can make absorption of odors to the olfactory epithelium by diffusion through the mucus layer. The odors then act on the chemo-sensitive epithelium of olfactory sensory neurons (OSNs). Therefore, any pathological changes in the olfactory area, for instance, dry nose caused by Sjögren's Syndrome (SS) may interfere with olfactory function. SS is an autoimmune disease in which aquaporin (AQP) 5 autoantibodies have been detected in the serum. However, the expression of AQP5 in olfactory mucosa and its function in olfaction is still unknown. Based on the study of the expression characteristics of AQP5 protein in the nasal mucosa, the olfaction dysfunction in AQP5 knockout (KO) mice was found by olfactory behavior analysis, which was accompanied by reduced secretion volume of Bowman's gland by using in vitro secretion measure system, and the change of acid mucin in nasal mucus layer was identified. By excluding the possibility that olfactory disturbance was caused by changes in OSNs, the result indicated that AQP5 contributes to olfactory functions by regulating the volume and composition of OE mucus layer, which is the medium for the dissolution of odor molecules. Our results indicate that AQP5 can affect the olfactory functions by regulating the water supply of BGs and the mucus layer upper the OE that can explain the olfactory loss in the patients of SS, and AQP5 KO mice might be used as an ideal model to study the olfactory dysfunction.
Assuntos
Transtornos do Olfato , Síndrome de Sjogren , Camundongos , Humanos , Animais , Olfato , Mucosa Olfatória/metabolismo , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Aquaporina 5/genética , Aquaporina 5/metabolismo , Transtornos do Olfato/genética , Transtornos do Olfato/metabolismoRESUMO
Olfactory epithelium, which detects and transmits odor signals, is critical for the function of olfactory system. Olfactory epithelium is able to recover spontaneously after injury under normal circumstances, but this ability is dampened in certain diseases or senility, which causes olfactory dysfunction. The olfactory epithelium consists of basal cells, sustentacular cells and olfactory sensory neurons. In order to develop an olfactory epithelial organoid containing multiple olfactory cell types in vitro, we used three-dimensional culture model and small molecules screening. This organoid system consists of horizontal basal-like cells, globose basal-like cells, sustentacular-like cells and olfactory sensory neurons-like cells. Through statistical analysis of clone diameter, immunofluorescence staining and qPCR detection of the expression level of related marker genes. We identified a series of growth factors and small molecule compounds that affected the proliferation, composition and gene expression of the organoids. CHIR-99021, an activator of Wnt signaling pathway, increased the colony formation and proliferation rate of olfactory epithelial organoids and the expression level of marker genes of olfactory sensory neurons-like cells. In addition, each factor in the culture system increased the proportion of c-Kit-positive globose basal-like cell colonies in organoids. Moreover, EGF and vitamin C were both beneficial to the expression of horizontal basal-like cell marker genes in organoids. The established olfactory epithelial organoid system mimicked the process of olfactory epithelial stem cells differentiating into various olfactory epithelial cell types, thus providing a research model for studying olfactory epithelial tissue regeneration, the pathological mechanism of olfactory dysfunction and drug screening for olfactory dysfunction treatment.
Assuntos
Transtornos do Olfato , Mucosa Olfatória , Humanos , Mucosa Olfatória/metabolismo , Células Epiteliais , Organoides/metabolismo , Transtornos do Olfato/metabolismoRESUMO
Olfactory dysfunction is an early symptom of neurodegenerative disease. Amyloid-beta oligomers (AßOs), the pathologic protein of Alzheimer's disease (AD), have been confirmed to be firstly deposited in olfactory bulb (OB), causing smell to malfunction. However, the detailed mechanisms underlying pathogenic nature of AßOs-induced olfactory neuronal degeneration in AD are not completely realized. Here, an early-stage olfactory dysfunction pathological model of AD in vitro based on biomimetic OB neuronal network chip was established for dynamic multi-site detection of neuronal electrical activity and network connection. We found both spike firing and correlation of overall neuronal network change regularly displayed gradually active state and then rapidly decay state after AßOs induction. Moreover, MK-801 and memantine were administrated at early-stage to detect alteration of OB neurons simulating nasal administration for AD treatment, which showed an almost recovery through the intermittent firing pattern. Together, this neuronal network-on-chip has revealed synaptic impairment and network neurodegeneration of olfactory dysfunction in AD, providing potential mechanisms information for early-stage progressive olfactory amyloidogenic pathology.
Assuntos
Doença de Alzheimer , Técnicas Biossensoriais , Doenças Neurodegenerativas , Transtornos do Olfato , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomimética , Maleato de Dizocilpina/metabolismo , Humanos , Memantina/metabolismo , Neurônios/metabolismo , Transtornos do Olfato/etiologia , Transtornos do Olfato/metabolismo , Transtornos do Olfato/patologia , Bulbo Olfatório , OlfatoRESUMO
Background. For neurodegenerative diseases such as Huntington's disease (HD), early diagnosis is essential to treat patients and delay symptoms. Impaired olfaction, as observed as an early symptom in Parkinson´s disease, may also constitute a key symptom in HD. However, there are few reports on olfactory deficits in HD. Therefore, we aimed to investigate, in a transgenic rat model of HD: (1) whether general olfactory impairment exists and (2) whether there are disease-specific dynamics of olfactory dysfunction when the vomeronasal (VNE) and main olfactory epithelium (MOE) are compared. Methods. We used male rats of transgenic line 22 (TG22) of the bacterial artificial chromosome Huntington disease model (BACHD), aged 3 days or 6 months. Cell proliferation, apoptosis and macrophage activity were examined with immunohistochemistry in the VNE and MOE. Results. No differences were observed in cellular parameters in the VNE between the groups. However, the MOE of the 6-month-old HD animals showed a significantly increased number of mature olfactory receptor neurons. Other cellular parameters were not affected. Conclusions. The results obtained in the TG22 line suggest a relative stability in the VNE, whereas the MOE seems at least temporarily affected.
Assuntos
Doença de Huntington , Transtornos do Olfato , Neurônios Receptores Olfatórios , Animais , Cromossomos Artificiais Bacterianos , Modelos Animais de Doenças , Doença de Huntington/metabolismo , Masculino , Transtornos do Olfato/metabolismo , Mucosa Olfatória/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Ratos , Ratos TransgênicosRESUMO
BACKGROUNDPresbyosmia, or aging-related olfactory loss, occurs in a majority of humans over age 65 years, yet remains poorly understood, with no specific treatment options. The olfactory epithelium (OE) is the peripheral organ for olfaction and is subject to acquired damage, suggesting a likely site of pathology in aging. Adult stem cells reconstitute the neuroepithelium in response to cell loss under normal conditions. In aged OE, patches of respiratory-like metaplasia have been observed histologically, consistent with a failure in normal neuroepithelial homeostasis.MethodsAccordingly, we have focused on identifying cellular and molecular changes in presbyosmic OE. The study combined psychophysical testing with olfactory mucosa biopsy analysis, single-cell RNA-Sequencing (scRNA-Seq), and culture studies.ResultsWe identified evidence for inflammation-associated changes in the OE stem cells of presbyosmic patients. The presbyosmic basal stem cells exhibited increased expression of genes involved in response to cytokines or stress or the regulation of proliferation and differentiation. Using a culture model, we found that cytokine exposure drove increased TP63, a transcription factor acting to prevent OE stem cell differentiation.ConclusionsOur data suggest aging-related inflammatory changes in OE stem cells may contribute to presbyosmia via the disruption of normal epithelial homeostasis. OE stem cells may represent a therapeutic target for restoration of olfaction.FundingNIH grants DC018371, NS121067, DC016224; Office of Physician-Scientist Development, Burroughs-Wellcome Fund Research Fellowship for Medical Students Award, Duke University School of Medicine.
Assuntos
Envelhecimento/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica , Transtornos do Olfato/metabolismo , Mucosa Olfatória/metabolismo , Células-Tronco/metabolismo , Idoso , Idoso de 80 Anos ou mais , Células Epiteliais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVES: Exosomal Phospho-Tau-181(P-T181-tau), Total tau (T-tau), and amyloid-ß peptide 42 (Aß42) have been proved the capacity for the amnestic mild cognitive impairment (MCI) and the diagnosis of Alzheimer's disease (AD). This study aimed to explore the cognitive function and the levels of P-T181-tau, T-tau, and Aß42 in neuronal-derived exosomes (NDEs) extracted from plasma in normal cognitive adults over 45 years old with olfactory dysfunction. METHODS: A cross-sectional survey of 29 participants aged over 45 was conducted. Plasma exosomes were isolated, precipitated, and enriched by immuno-absorption with anti- L1 cell adhesion molecule (L1CAM) antibody. NDEs were characterized by CD81, and extracted NDE protein (P-T181-tau, T-tau, and Aß42) biomarkers were quantified by enzyme-linked immunosorbent assay (ELISAs). Olfactory performance was assessed by Sniffin' Sticks and cognitive performance was assessed by Montreal Cognitive Assessment (MoCA). RESULTS: There was no significant difference between adults with olfactory dysfunction and without olfactory dysfunction regarding the cognitive function as measured by MoCA and all the participants showed normal cognition. Adults with olfactory dysfunction showed a higher concentration of P-T181-tau in plasma NDEs than did adults without olfactory dysfunction (P = 0.034). Both the levels of P-T181-tau (r = - 0.553, P = 0.003) and T-tau (r = - 0.417, P = 0.034) negatively correlated with the odor identification scores. In addition, the level of T-tau negatively correlated with MoCA scores (r = - 0.597, P = 0.002). The levels of P-T181-tau (r = - 0.464, P = 0.022) and T-tau (r = - 0.438, P = 0.032) negatively correlated with the delayed recall scores. CONCLUSIONS: This study demonstrated that cognition-related pathogenic proteins including P-T181-tau in plasma NDEs were significantly increased in adults over 45 years old with olfactory dysfunction before the occurrence of cognitive impairment. The impaired odor identification and the delayed recall function were highly associated with the increased levels of P-T181-tau and T-tau in plasma NDEs.
Assuntos
Cognição , Exossomos , Transtornos do Olfato , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Biomarcadores , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Exossomos/metabolismo , Humanos , Pessoa de Meia-Idade , Transtornos do Olfato/metabolismo , Fragmentos de Peptídeos/metabolismoRESUMO
BACKGROUND: It remains unclear whether the metabolic activity of nasal mucus in the olfactory and respiratory areas is different. Moreover, age- and olfaction-related changes may affect metabolism. METHODS: Hexanal, octanal, and 2-methylbutanal were selected for in vitro metabolism analysis and compared between the olfactory cleft and respiratory mucus of participants < 50-year-old with normal olfaction using gas chromatography mass spectrometry. The metabolic activity of hexanal in the olfactory cleft mucus was further compared between three groups, (1) normal olfaction, age < 50 years old, (2) normal olfaction, age ≥50 years old, and (3) idiopathic olfactory impairment. To characterize the enzyme(s) responsible for aldehyde reduction, we also tested if epalr22897estat and 3,5-dichlorosalicylic acid, types of reductase inhibitors, affect metabolism. RESULTS: Conversion of aldehydes to their corresponding alcohols was observed in the olfactory cleft and respiratory mucus. The metabolic production of hexanol, octanol, and 2-methybutanol was significantly higher in the olfactory cleft mucus than in the respiratory mucus (p < 0.01). The metabolic conversion of hexanal to hexanol in the mucus of the idiopathic olfactory impairment group was significantly lower than that in the age-matched normal olfaction group. Excluding the nicotinamide adenine dinucleotide phosphate (NADPH) regenerating system from the reaction mixture inhibited metabolism. The addition of either epalr22897estat or 3,5-dichlorosalicylic acid did not inhibit this metabolic conversion. CONCLUSIONS: The enzymatic metabolism of odorants in the olfactory cleft mucus is markedly higher than in the respiratory mucus and decreases in patients with idiopathic olfactory impairment.
Assuntos
Odorantes , Transtornos do Olfato , Voluntários Saudáveis , Hexanóis/metabolismo , Humanos , Pessoa de Meia-Idade , Muco/metabolismo , Odorantes/análise , Transtornos do Olfato/metabolismo , OlfatoRESUMO
The olfactory system has become an important functional gateway to understand and analyze neuromodulation since olfactory dysfunction and deficits have emerged as prodromal and, at other times, as first symptoms of many of neurodegenerative, neuropsychiatric and communication disorders. Considering olfactory dysfunction as outcome of altered, damaged and/or inefficient olfactory processing, in the current review, we analyze how olfactory processing interacts with the endocannabinoid signaling system. In the human body, endocannabinoid synthesis is a natural and on-demand response to a wide range of physiological and environmental stimuli. Our current understanding of the response dynamics of the endocannabinoid system is based in large part on research advances in limbic system areas, such as the hippocampus and the amygdala. Functional interactions of this signaling system with olfactory processing and associated pathways are just emerging but appear to grow rapidly with multidimensional approaches. Recent work analyzing the crystal structure of endocannabinoid receptors bound to their agonists in a signaling complex has opened avenues for developing specific therapeutic drugs that could help with neuroinflammation, neurodegeneration, and alleviation/reduction of pain. We discuss the role of endocannabinoids as signaling molecules in the olfactory system and the relevance of the endocannabinoid system for synaptic plasticity.
Assuntos
Endocanabinoides , Transtornos do Olfato , Endocanabinoides/metabolismo , Humanos , Plasticidade Neuronal/fisiologia , Transtornos do Olfato/metabolismo , Bulbo Olfatório/metabolismo , Olfato/fisiologiaRESUMO
The nasal mucosa (NM) contains olfactory mucosa which contributes to the detection of odorant molecules and the transmission of olfactory information to the brain. To date, the lipid composition of the human NM has not been adequately characterized. Using gas chromatography, liquid chromatography coupled to mass spectrometry and thin layer chromatography, we analyzed the fatty acids and the phospholipid and ceramide molecular species in adult human nasal and blood biopsies. Saturated and polyunsaturated fatty acids (PUFAs) accounted for 45% and 29% of the nasal total fatty acids, respectively. Fatty acids of the n-6 family were predominant in the PUFA subgroup. Linoleic acid and arachidonic acid (AA) were incorporated in the main nasal phospholipid classes. Correlation analysis revealed that the nasal AA level might be positively associated with olfactory deficiency. In addition, a strong positive association between the AA levels in the NM and in plasma cholesteryl esters suggested that this blood fraction might be used as an indicator of the nasal AA level. The most abundant species of ceramides and their glycosylated derivatives detected in NM contained palmitic acid and long-chain fatty acids. Overall, this study provides new insight into lipid species that potentially contribute to the maintenance of NM homeostasis and demonstrates that circulating biomarkers might be used to predict nasal fatty acid content.
Assuntos
Ácidos Graxos/metabolismo , Lipidômica , Transtornos do Olfato/metabolismo , Mucosa Olfatória/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by movement dysfunction due to selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. Non-motor symptoms of PD (e.g., sensory dysfunction, sleep disturbance, constipation, neuropsychiatric symptoms) precede motor symptoms, appear at all stages, and impact the quality of life, but they frequently go unrecognized and remain untreated. Even when identified, traditional dopamine replacement therapies have little effect. We discuss here the pathology of two PD-associated non-motor symptoms: olfactory dysfunction and depression. Olfactory dysfunction is one of the earliest non-motor symptoms in PD and predates the onset of motor symptoms. It is accompanied by early deposition of Lewy pathology and neurotransmitter alterations. Because of the correlation between olfactory dysfunction and an increased risk of progression to PD, olfactory testing can potentially be a specific diagnostic marker of PD in the prodromal stage. Depression is a prevalent PD-associated symptom and is often associated with reduced quality of life. Although the pathophysiology of depression in PD is unclear, studies suggest a causal relationship with abnormal neurotransmission and abnormal adult neurogenesis. Here, we summarize recent progress in the pathology of the non-motor symptoms of PD, aiming to provide better guidance for its effective management.
Assuntos
Depressão/diagnóstico , Transtornos do Olfato/diagnóstico , Doença de Parkinson/diagnóstico , Sintomas Prodrômicos , Animais , Depressão/metabolismo , Depressão/terapia , Dopamina/metabolismo , Diagnóstico Precoce , Humanos , Transtornos do Olfato/metabolismo , Transtornos do Olfato/terapia , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Resultado do TratamentoRESUMO
Olfactory dysfunction (OD) is a highly frequent early non-motor symptom of Parkinson's disease (PD). An important step to potentially use OD for the development of early diagnostic tools of PD is to differentiate PD-related OD from other forms of non-parkinsonian OD (NPOD: postviral, sinunasal, post-traumatic, and idiopathic OD). Measuring non-olfactory chemosensory modalities, especially the trigeminal system, may allow to characterize a PD-specific olfactory profile. We here review the literature on PD-specific chemosensory alteration patterns compared with NPOD. Specifically, we focused on the impact of PD on the trigeminal system and particularly on the interaction between olfactory and trigeminal systems. As this interaction is seemingly affected in a disease-specific manner, we propose a model of interaction between both chemosensory systems that is distinct for PD-related OD and NPOD. These patterns of chemosensory impairment still need to be confirmed in prodromal PD; nevertheless, appropriate chemosensory tests may eventually help to develop diagnostic tools to identify individuals at risks for PD.
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Transtornos do Olfato/metabolismo , Doença de Parkinson/metabolismo , Nervo Trigêmeo/metabolismo , Humanos , Doença de Parkinson/diagnósticoRESUMO
Olfactory dysfunction is a common disorder in the general population. There are multiple causes, one of which being ciliopathies, an emerging class of human hereditary genetic disorders characterized by multiple symptoms due to defects in ciliary biogenesis, maintenance, and/or function. Mutations/deletions in a wide spectrum of ciliary genes have been identified to cause ciliopathies. Currently, besides symptomatic therapy, there is no available therapeutic treatment option for olfactory dysfunction caused by ciliopathies. Multiple studies have demonstrated that targeted gene replacement can restore the morphology and function of olfactory cilia in olfactory sensory neurons and further re-establish the odor-guided behaviors in animals. Therefore, targeted gene replacement could be potentially used to treat olfactory dysfunction in ciliopathies. However, due to the potential limitations of single-gene therapy for polygenic mutation-induced diseases, alternative therapeutic targets for broader curative measures need to be developed for olfactory dysfunction, and also for other symptoms in ciliopathies. Here we review the current understanding of ciliogenesis and maintenance of olfactory cilia. Furthermore, we emphasize signaling mechanisms that may be involved in the regulation of olfactory ciliary length and highlight potential alternative therapeutic targets for the treatment of ciliopathy-induced dysfunction in the olfactory system and even in other ciliated organ systems.
Assuntos
Ciliopatias/genética , Ciliopatias/terapia , Terapia Genética , Transtornos do Olfato/genética , Transtornos do Olfato/terapia , Animais , Ciliopatias/metabolismo , Humanos , Transtornos do Olfato/metabolismoRESUMO
BACKGROUND: Olfactory impairment is evident in Alzheimer's disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. OBJECTIVE: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. METHODS: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-ß (Aß42). RESULTS: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (pâ<â0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (pâ<â0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (pâ<â0.01). CONCLUSION: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.NCT Registration Numbers: NCT03373604; NCT02831283.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Transtornos do Olfato/etiologia , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/metabolismo , Transtornos do Olfato/patologia , Tomografia por Emissão de PósitronsRESUMO
OBJECTIVE: The novel coronavirus disease-19 (COVID-19) pandemic had intense social and economic effects. Patients infected with COVID-19 may present with a series of conditions. A considerable number of patients express taste and smell disturbances as a prodromal, coexistent, or as the only manifestation of COVID-19 infection. The objective of the present review is to review the hypothetical mechanisms of action and etiopathogenesis of dysgeusia in COVID-19 patients. MATERIALS AND METHODS: Multiple scientific databases were explored, including PubMed, Medline, Scopus, Cochrane-library, LILACS, Livivo and OpenGrey. All types of articles that discussed the pathogenesis of dysgeusia were included, while articles that described dysgeusia without detail about its mode of action were excluded. RESULTS: A total of 47 articles, with different designs, were included in this review. These articles suggested direct viral neural invasion to olfactory and gustatory nerves, viral cytotoxicity to taste buds, angiotensin II imbalance, augmented pro-inflammatory cytokines, and disturbances in salivary glands and sialic acid. COVID-19 induced-dysgeusia was also associated with systemic diseases, medications, zinc, chemicals, and disinfectants. CONCLUSIONS: The most likely cause of transient dysgeusia in COVID-19 is peripheral neurotropism and direct toxicity to taste buds or olfactory epithelium. Other factors may also play a contributory role in dysgeusia, such as a defect in the quality and quantity of saliva, pro-inflammatory cytokines, angiotensin II accumulation, systemic diseases, hypozincemia, and excessive use of chemicals.
Assuntos
COVID-19/complicações , COVID-19/metabolismo , Disgeusia/etiologia , Disgeusia/metabolismo , Ageusia/diagnóstico , Ageusia/etiologia , Ageusia/metabolismo , COVID-19/diagnóstico , Disgeusia/diagnóstico , Humanos , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/etiologia , Transtornos do Olfato/metabolismo , Estudos Prospectivos , Sistema Renina-Angiotensina/fisiologia , Estudos Retrospectivos , Olfato/fisiologia , Paladar/fisiologiaRESUMO
Convergent lines of evidence indicate a striking correlation between olfactory deficits and depressive symptoms. However, the effectiveness of intranasal treatment of antidepressant or other neurotrophic agents remains poorly understanding. Here in this study, we created depression mouse model and explored the antidepressant effects of GLP-1 analog lixisenatide (LXT) with intranasal treatment. Consecutive intranasal treatment of LXT remarkably reduced the depressive and anxiety behaviors. Meanwhile, it also improved the olfactory memory and olfactory sensitivity. Immunofluorescent analysis demonstrated the LXT improved the adult neurogenesis in olfactory system and hippocampus. Inhibition of adult neurogenesis with TMZ caused the compromised effects of LXT in improving emotional and olfactory functions, suggesting the vital role of adult neurogenesis in LXT induced depression therapeutic effects. Treatment of LXT resulted in the increased phosphorylation of CREB protein in hippocampal tissue, indicating CREB plays important roles in antidepressant effects of LXT intranasal treatment. Inhibiting CREB with chemical approach decreased effects of LXT in reserving depression induced emotional and olfactory functions. In conclusion, our study suggests intranasal treatment of LXT could be a potential antidepressant to improve the olfactory functions as well as the emotional behaviors.