Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

2021 ◽  
Author(s):  
Jeffrey R Atkinson ◽  
Andrew D Jerome ◽  
Andrew R Sas ◽  
Ashley Munie ◽  
William David Arnold ◽  
...  
Keyword(s):  
Adoptive Transfer ◽  
Microglial Activation ◽  
Demyelinating Disease ◽  
Clinical Course ◽  
Dominant Role ◽  
Biological Aging ◽  
Middle Aged ◽  
Adult Mice ◽  
Age Related ◽  
Bone Marrow Chimeras

Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing remitting MS (RRMS) typically presents in the third or fourth decade, while the mean age of presentation of progressive MS (pMS) is 45 years old. Here we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, is more severe, and less like to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils are more abundant, while B cells are relatively sparse, in central nervous system (CNS) infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrate that radio-resistant, non-hematopoietic cells play a dominant role in shaping age-related features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of pMS, EAE in middle-aged adoptive transfer recipients is characterized by widespread microglial activation. Microglia from older mice express a distinctive transcriptomic profile, suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.

Abstract 123: Age-Related Diminishment of the Subventricular Zone Cytogenic Response and Its Contributions to Motor Recovery After Cortical Infarcts

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Michael R Williamson ◽  
Stephanie Le ◽  
Ronald L Franzen ◽  
Michael R Drew ◽  
Theresa A Jones
Keyword(s):  
Young Adult ◽  
Subventricular Zone ◽  
Motor Recovery ◽  
Lineage Tracing ◽  
Stem Cell Markers ◽  
Middle Aged ◽  
Reaching Task ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related

Stroke increases proliferation within the subventricular zone (SVZ) cytogenic niche and causes subsequent migration of newborn cells towards the site of injury. We investigated the functional consequences of age-related blunting of the SVZ cytogenic response to ischemia. We found that there was a marked reduction in proliferation and neural stem cell markers within the SVZ of middle aged (aged 12-16 months) versus young adult (aged 3-5 months) mice in the intact brain and after photothrombotic infarcts in motor cortex. Using an inducible, heritable lineage tracing system (Nestin-CreER T2 :: Ai14 mice) to quantify SVZ-derived neural precursor cells (NPCs) that migrated towards the infarct, we found that there was a considerable age-related reduction in the number of NPCs in peri-infarct cortex. These findings indicate a marked diminishment of SVZ NPC proliferation and migration after focal ischemia by middle age. Next, we assessed the contributions of the SVZ cytogenic response to recovery of skilled motor function. We used glial fibrillary acidic protein-thymidine kinase mice to conditionally ablate NPCs with ganciclovir administration. In young adult mice, NPC ablation significantly impaired recovery of motor performance on the single seed reaching task after motor cortical infarcts. By contrast, NPC ablation did not affect motor recovery in middle aged mice. Importantly, the magnitude of recovery was less in middle aged mice—regardless of NPC ablation—than in control young adult mice. Middle aged mice recovered similarly to young adult mice lacking NPCs. These results indicate that SVZ cytogenesis contributes to functional improvements after cortical infarcts and that the diminishment of the cytogenic response with age may be implicated in age-related worsening of outcome after stroke. Restoration of SVZ cytogenesis in aged animals might improve behavioral recovery.

scholarly journals Healthy Brain Aging Modifies Microglial Calcium Signaling In Vivo

2019 ◽  
Vol 20 (3) ◽  
pp. 589 ◽  
Author(s):  
Maria Olmedillas del Moral ◽  
Nithi Asavapanumas ◽  
Néstor Uzcátegui ◽  
Olga Garaschuk
Keyword(s):  
Young Adult ◽  
Brain Aging ◽  
Critical Role ◽  
Low Grade ◽  
Middle Aged ◽  
Senescent Phenotype ◽  
Adult Mice ◽  
Age Related ◽  
Old Mice

Brain aging is characterized by a chronic, low-grade inflammatory state, promoting deficits in cognition and the development of age-related neurodegenerative diseases. Malfunction of microglia, the brain-resident immune cells, was suggested to play a critical role in neuroinflammation, but the mechanisms underlying this malfunctional phenotype remain unclear. Specifically, the age-related changes in microglial Ca2+ signaling, known to be linked to its executive functions, are not well understood. Here, using in vivo two-photon imaging, we characterize intracellular Ca2+ signaling and process extension of cortical microglia in young adult (2–4-month-old), middle-aged (9–11-month-old), and old (18–21-month-old) mice. Our data revealed a complex and nonlinear dependency of the properties of intracellular Ca2+ signals on an animal’s age. While the fraction of cells displaying spontaneous Ca2+ transients progressively increased with age, the frequencies and durations of the spontaneous Ca2+ transients followed a bell-shaped relationship, with the most frequent and largest Ca2+ transients seen in middle-aged mice. Moreover, in old mice microglial processes extending toward an ATP source moved faster but in a more disorganized manner, compared to young adult mice. Altogether, these findings identify two distinct phenotypes of aging microglia: a reactive phenotype, abundantly present in middle-aged animals, and a dysfunctional/senescent phenotype ubiquitous in old mice.

scholarly journals Absence of TGFβ signaling in retinal microglia induces retinal degeneration and exacerbates choroidal neovascularization

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Wenxin Ma ◽  
Sean M Silverman ◽  
Lian Zhao ◽  
Rafael Villasmil ◽  
Maria M Campos ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Microglial Activation ◽  
Retinal Disease ◽  
Age Related Macular Degeneration ◽  
Tgfβ Signaling ◽  
Adult Mice ◽  
Age Related ◽  
Retinal Microglia ◽  
Tgfβ Receptor ◽  
Activation Status

Constitutive TGFβ signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFβ signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFβ receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFβ-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFβ signaling as a potential therapeutic target.

scholarly journals Effect of chronic intranasal administration of α-synuclein oligomers on motor activity and anxiety in adult and middle-aged mice

2019 ◽  
pp. 34-40
Author(s):  
О.А. Соловьева ◽  
М.А. Грудень ◽  
В.В. Шерстнев
Keyword(s):  
Motor Activity ◽  
Motor Behavior ◽  
Lewy Body Dementia ◽  
Chronic Administration ◽  
Middle Aged ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Plus Maze ◽  
Age Dependent

К числу наименее экспериментально изученных аспектов патогенеза α-синуклеинопатий (основными представителями которых являются болезнь Паркинсона и деменция с тельцами Леви) относятся возрастные особенности влияния амилоидогенных форм α-синуклеина, образующихся в результате его гиперэкспрессии и мисфолдинга, на поведение и физиологические функции млекопитающих. Цель исследования состояла в изучении влияния олигомеров α-синуклеина на двигательную активность и тревожность взрослых и стареющих мышей. Материалы и методы. Опыты проводили на 6- и 12-месячных самцах мышей C57Bl/6, которым на протяжении 14 дней один раз в сутки вводили раствор олигомеров α-синуклеина (суммарная доза 0,48 мг/кг) или физиологический раствор. Для оценки общей двигательной активности и тревожности использовали тесты «Открытое поле» и «Приподнятый крестообразный лабиринт». Результаты. Обнаружено, что олигомеры α-синуклеина при хроническом введении вызывают у взрослых мышей возрастание тревожности без общих двигательных нарушений, в то время как у стареющих мышей - нарушение двигательной активности (снижение средней скорости и длины пройденного пути) и рост тревожности. Выводы. Полученные данные свидетельствуют о возраст зависимом характере поведенческих эффектов олигомеров α-синуклеина в условиях хронического интраназального введения. Among the least experimentally studied aspects of the pathogenesis of α- synucleinopathies (major representatives, Parkinson`s disease and Lewy body dementia) are age-related effects of amyloidogenic α-synuclein species resulting from overexpression and misfolding on mammalian behavior and physiological functions. The aim of this study was to evaluate effects of α-synuclein oligomers on motor behavior and anxiety in adult and middle-aged mice. Methods. Experiments were performed on 6- and 12-month-old male C57Bl/6 mice. A solution of α-synuclein oligomers or saline was administered once a day for 14 days (total dose, 0.48 mg/kg). To evaluate the overall motor activity and anxiety, the open field and elevated plus maze tests were used. Results. Chronic administration of α-synuclein oligomers to adult mice increased anxiety without overall motor disorders while middle-aged mice demonstrated both changes in their motor activity (decreases in average speed and path length) and increased anxiety. Conclusions. The study showed that the behavioral effects of α-synuclein oligomers administered chronically, intranasally were age-dependent.

scholarly journals Activation of autophagy ameliorates age-related neurogenesis decline and neurodysfunction in adult mice

2021 ◽  
Author(s):  
na yang ◽  
Xue-qin Liu ◽  
Xiao-jie Niu ◽  
Xiao-qiang Wang ◽  
Rong Jiang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Adult Neurogenesis ◽  
Neural Progenitor Cells ◽  
Normal Function ◽  
Mammalian Brain ◽  
Middle Aged ◽  
Adult Mice ◽  
Age Related ◽  
Sirna Interference ◽  
Shed Light

Abstract Adult neurogenesis is the ongoing generation of functional new neurons from neural progenitor cells (NPCs) in the mammalian brain. However, this process declines with aging, which is implicated in the recession of brain function and neurodegeneration. Understanding the mechanism of adult neurogenesis and stimulating it will benefit the mitigation of neurodegenerative diseases. Autophagy, a highly conserved process of cellular degradation, is essential for maintaining cellular homeostasis and normal function. Whether and how autophagy affects adult neurogenesis remains poorly understood. In present study, we revealed a close connection between impaired autophagy and adult neurogenetic decline. Expression of autophagy-related genes and autophagic activity were significantly declined in the middle-aged subventricular/subgranular zone (SVZ/SGZ) homogenates and cultured NPCs, and inhibiting autophagy by siRNA interference resulted in impaired pluripotency of NPCs. Conversely, stimulating autophagy by rapamycin not only revitalized the viability and pluripotency of middle-aged NPCs, but also facilitated the neurogenesis in middle-aged SVZ/SGZ. More importantly, autophagic activation by rapamycin also ameliorated the olfactory sensitivity and cognitional capacities in middle-aged mice. Taken together, our results reveal that compromised autophagy is involved in the decline of adult neurogenesis, which could be reversed by autophagy activation. It also shed light on the regulation of adult neurogenesis and paves the way for developing therapeutic strategy for aging and neurodegenerative diseases.

scholarly journals Inflamm-Aging Is Associated with Lower Plasma PTX3 Concentrations and an Impaired Capacity of PBMCs to Express hTERT following LPS Stimulation

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Aaron L. Slusher ◽  
Tiffany M. Zúñiga ◽  
Edmund O. Acevedo
Keyword(s):  
Gene Expression ◽  
Young Adults ◽  
Telomere Length ◽  
Immune Cell ◽  
Ex Vivo ◽  
Middle Aged ◽  
Human Telomerase Reverse Transcriptase ◽  
Negatively Associated ◽  
Htert Gene ◽  
Age Related

Age-related elevations in proinflammatory cytokines, known as inflamm-aging, are associated with shorter immune cell telomere lengths. Purpose. This study examined the relationship of plasma PTX3 concentrations, a biomarker of appropriate immune function, with telomere length in 15 middle-aged (40-64 years) and 15 young adults (20-31 years). In addition, PBMCs were isolated from middle-aged and young adults to examine their capacity to express a key mechanistic component of telomere length maintenance, human telomerase reverse transcriptase (hTERT), following ex vivo cellular stimulation. Methods. Plasma PTX3 and inflammatory cytokines (i.e., IL-6, IL-10, TGF-β, and TNF-α), PBMC telomere lengths, and PBMC hTERT gene expression and inflammatory protein secretion following exposure to LPS, PTX3, and PTX3+LPS were measured. Results. Aging was accompanied by the accumulation of centrally located visceral adipose tissue, without changes in body weight and BMI, and alterations in the systemic inflammatory milieu (decreased plasma PTX3 and TGF-β; increased TNF-α (p≤0.050)). In addition, shorter telomere lengths in middle-aged compared to young adults (p=0.011) were negatively associated with age, body fat percentages, and plasma TNF-α (r=−0.404, p=0.027; r=−0.427, p=0.019; and r=−0.323, p=0.041, respectively). Finally, the capacity of PBMCs to increase hTERT gene expression following ex vivo stimulation was impaired in middle-aged compared to young adults (p=0.033) and negatively associated with telomere lengths (r=0.353, p=0.028). Conclusions. Proinflammation and the impaired hTERT gene expression capacity of PBMCs may contribute to age-related telomere attrition and disease.

scholarly journals The Prevalence of Inorganic Mercury in Human Kidneys Suggests a Role for Toxic Metals in Essential Hypertension

Toxics ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 67
Author(s):  
Roger Pamphlett ◽  
Philip A. Doble ◽  
David P. Bishop
Keyword(s):  
Essential Hypertension ◽  
Toxic Metals ◽  
Inductively Coupled Plasma ◽  
Dominant Role ◽  
Inorganic Mercury ◽  
Experimental Studies ◽  
Human Kidney ◽  
Proximal Tubules ◽  
Age Related ◽  
Icp Ms

The kidney plays a dominant role in the pathogenesis of essential hypertension, but the initial pathogenic events in the kidney leading to hypertension are not known. Exposure to mercury has been linked to many diseases including hypertension in epidemiological and experimental studies, so we studied the distribution and prevalence of mercury in the human kidney. Paraffin sections of kidneys were available from 129 people ranging in age from 1 to 104 years who had forensic/coronial autopsies. One individual had injected himself with metallic mercury, the other 128 were from varied clinicopathological backgrounds without known exposure to mercury. Sections were stained for inorganic mercury using autometallography. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used on six samples to confirm the presence of autometallography-detected mercury and to look for other toxic metals. In the 128 people without known mercury exposure, mercury was found in: (1) proximal tubules of the cortex and Henle thin loops of the medulla, in 25% of kidneys (and also in the man who injected himself with mercury), (2) proximal tubules only in 16% of kidneys, and (3) Henle thin loops only in 23% of kidneys. The age-related proportion of people who had any mercury in their kidney was 0% at 1–20 years, 66% at 21–40 years, 77% at 41–60 years, 84% at 61–80 years, and 64% at 81–104 years. LA-ICP-MS confirmed the presence of mercury in samples staining with autometallography and showed cadmium, lead, iron, nickel, and silver in some kidneys. In conclusion, mercury is found commonly in the adult human kidney, where it appears to accumulate in proximal tubules and Henle thin loops until an advanced age. Dysfunctions of both these cortical and medullary regions have been implicated in the pathogenesis of essential hypertension, so these findings suggest that further studies of the effects of mercury on blood pressure are warranted.

scholarly journals Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rahul Basu ◽  
Vinod Nair ◽  
Clayton W. Winkler ◽  
Tyson A. Woods ◽  
Iain D. C. Fraser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Virus Infection ◽  
La Crosse Virus ◽  
Brain Capillary ◽  
Adult Mice ◽  
Age Related ◽  
Capillary Endothelial Cells ◽  
The Brain

Abstract Background A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. Methods To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. Results BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. Conclusions These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease.

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