Sex- and age‐dependent alterations of splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice

Abstract Background Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

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Insights into the multifaceted role of circular RNAs: implications for Parkinson’s disease pathogenesis and diagnosis

npj Parkinson s Disease ◽

10.1038/s41531-021-00265-9 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Epaminondas Doxakis

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rna Binding ◽

Rna Binding Proteins ◽

Clinical Manifestations ◽

Alpha Synuclein ◽

Circular Rnas ◽

Age Related ◽

And Function ◽

The Brain

AbstractParkinson’s disease (PD) is a complex, age-related, neurodegenerative disease whose etiology, pathology, and clinical manifestations remain incompletely understood. As a result, care focuses primarily on symptoms relief. Circular RNAs (circRNAs) are a large class of mostly noncoding RNAs that accumulate with aging in the brain and are increasingly shown to regulate all aspects of neuronal and glial development and function. They are generated by the spliceosome through the backsplicing of linear RNA. Although their biological role remains largely unknown, they have been shown to regulate transcription and splicing, act as decoys for microRNAs and RNA binding proteins, used as templates for translation, and serve as scaffolding platforms for signaling components. Considering that they are stable, diverse, and detectable in easily accessible biofluids, they are deemed promising biomarkers for diagnosing diseases. CircRNAs are differentially expressed in the brain of patients with PD, and growing evidence suggests that they regulate PD pathogenetic processes. Here, the biogenesis, expression, degradation, and detection of circRNAs, as well as their proposed functions, are reviewed. Thereafter, research linking circRNAs to PD-related processes, including aging, alpha-synuclein dysregulation, neuroinflammation, and oxidative stress is highlighted, followed by recent evidence for their use as prognostic and diagnostic biomarkers for PD.

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Significant Difference of Immune Cell Fractions and Their Correlations With Differential Expression Genes in Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.686066 ◽

2021 ◽

Vol 13 ◽

Author(s):

Yilin Huang ◽

Huisheng Liu ◽

Jiaqi Hu ◽

Chongyin Han ◽

Zhenggang Zhong ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

T Cells ◽

Nk Cells ◽

Cd4 T Cells ◽

Immune Cell ◽

Gamma Delta T Cells ◽

Expression Data ◽

Gamma Delta ◽

Cell Fractions

Parkinson’s disease (PD) is the second most neurodegenerative disease in the world. T cell infiltration in the central nervous system (CNS) has provided insights that the peripheral immune cells participate in the pathogenesis of PD. However, the association between the peripheral immune system and CNS remains to be elucidated. In this study, we analyzed incorporative substantia nigra (SN) expression data and blood expression data using the CIBERSORT to obtain the 22 immune cell fractions and then explored the molecular function to identify the potential key immune cell types and genes of PD. We observed that the proportions of naïve CD4 T cells, gamma delta T cells, resting natural killer (NK) cells, neutrophils in the blood, and regulatory T cells (Tregs) in the SN were significantly different between patients with PD and healthy controls (HCs). We identified p53-induced death domain protein 1 (PIDD1) as the hub gene of a PD-related module. The enrichment score of the neuron-specific gene set was significantly different between PD and HC, and genes in the neuron-related module were enriched in the biological process about mitochondria and synapses. These results suggested that the fractions of naïve CD4 T cells, gamma delta T cells, resting NK cells, and neutrophils may be used as a combined diagnostic marker in the blood, and Tregs in SN may be a potential therapeutic design target for PD.

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Specific immune status in Parkinson’s disease at different ages of onset

npj Parkinson s Disease ◽

10.1038/s41531-021-00271-x ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Jun Tian ◽

Shao-Bing Dai ◽

Si-Si Jiang ◽

Wen-Yi Yang ◽

Yi-Qun Yan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

T Cells ◽

Nk Cells ◽

Peripheral Blood ◽

Rating Scale ◽

Immune Status ◽

Immune Cell ◽

Late Onset ◽

Different Ages

AbstractRecent evidence suggests that innate and adaptive immunity play a crucial role in Parkinson’s disease (PD). However, studies regarding specific immune cell classification in the peripheral blood in PD remain lacking. Therefore, we aimed to explore the different immune status in patients with PD at different ages of onset. We included 22 patients; among them were 10 who had early-onset PD (EOPD) and 12 had late-onset PD (LOPD) and 10 young healthy controls (YHCs) and 8 elder HCs (EHCs). Mass cytometry staining technology was used to perform accurate immunotyping of cell populations in the peripheral blood. Motor symptoms and cognitive function were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) III score and Mini-mental State Examination (MMSE) score, respectively. T test and ANOVA statistical analysis were performed on the frequency of annotated cell population. Linear regression model was used to analyze the correlation between clusters and clinical symptoms. We characterized 60 cell clusters and discovered that the immune signature of PD consists of cluster changes, including decreased effector CD8+ T cells, lower cytotoxicity natural killer (NK) cells and increased activated monocytes in PD patients. In summary, we found that CD8+ T cells, NK cells, and monocytes were associated with PD. Furthermore, there may be some differences in the immune status of patients with EOPD and LOPD, suggesting differences in the pathogenesis between these groups.

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Investigation of Autosomal Genetic Sex Differences in Parkinson's disease

Annals of Neurology ◽

10.1002/ana.26090 ◽

2021 ◽

Author(s):

Cornelis Blauwendraat ◽

Hirotaka Iwaki ◽

Mary B. Makarious ◽

Sara Bandres‐Ciga ◽

Hampton Leonard ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Sex Differences

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The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

Scientific Reports ◽

10.1038/s41598-021-85510-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Megan C. Bakeberg ◽

Madison E. Hoes ◽

Anastazja M. Gorecki ◽

Frances Theunissen ◽

Abigail L. Pfaff ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Symptom Onset ◽

Disease Risk ◽

Age Of Onset ◽

Sequencing Analysis ◽

Age Related ◽

Australian Cohort ◽

Progression Markers ◽

Age Related Cognitive Decline

AbstractAbnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

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Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

Translational Stroke Research ◽

10.1007/s12975-021-00923-3 ◽

2021 ◽

Author(s):

Leoni Rolfes ◽

Tobias Ruck ◽

Christina David ◽

Stine Mencl ◽

Stefanie Bock ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Adoptive Transfer ◽

Immune Cell ◽

Nk Cell ◽

Cell Subset ◽

Neurological Deficits ◽

In Vitro Assays ◽

Experimental Stroke ◽

Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

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Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202366 ◽

2020 ◽

pp. 1-14

Author(s):

Shelby Shrigley ◽

Fredrik Nilsson ◽

Bengt Mattsson ◽

Alessandro Fiorenzano ◽

Janitha Mudannayake ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Lines ◽

Functional Recovery ◽

Embryonic Stem ◽

Hesc Line ◽

Alternative Source ◽

And Function

Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. Results: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

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Sex Differences in Parkinson's Disease Phenotype and Caregiving Disparities

Movement Disorders ◽

10.1002/mds.28459 ◽

2021 ◽

Vol 36 (2) ◽

pp. 526-526 ◽

Cited By ~ 1

Author(s):

Tomás Rosa ◽

Débora Amado Scerni ◽

Fúlvio Alexandre Scorza

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Sex Differences ◽

Disease Phenotype

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Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽

10.1177/17590914211009730 ◽

2021 ◽

Vol 13 ◽

pp. 175909142110097

Author(s):

Kui Cui ◽

Fan Yang ◽

Turan Tufan ◽

Muhammad U. Raza ◽

Yanqiang Zhan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transcription Factors ◽

Disease Model ◽

Neuronal Loss ◽

Mrna Levels ◽

Gene Therapies ◽

Protein Levels ◽

Dopaminergic Systems ◽

And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

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