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 Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

2018 ◽  
Author(s):  
Andrea KH Stavoe ◽  
Erika LF Holzbaur
Keyword(s):  
Young Adult ◽  
Late Onset ◽  
Transmembrane Protein ◽  
Autophagosome Formation ◽  
Common Risk Factor ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Assembly Kinetics ◽  
Exogenous Expression

SUMMARYAutophagy defects have been implicated in multiple late-onset neurodegenerative diseases. Since aging is the most common risk factor in neurodegeneration, we asked how autophagy is modulated in aging neurons. We compared the dynamics of autophagosome biogenesis in neurons from young adult and aged mice, identifying a significant decrease in biogenesis during aging. Autophagosome assembly kinetics are disrupted, with frequent production of stalled isolation membranes in neurons from aged mice; these precursors failed to resolve into LC3-positive autophagosomes. We did not detect alterations in the initial induction/nucleation steps of autophagosome formation. However, we found that the transmembrane protein Atg9 remained aberrantly associated with stalled isolation membranes, suggesting a specific disruption in the WIPI-dependent retrieval of Atg9. Depletion of WIPI2 from young neurons was sufficient to induce a similar deficit. Further, exogenous expression of WIPI2 in neurons from aged mice was sufficient to restore autophagosome biogenesis to the rates seen in neurons from young adult mice, suggesting a novel therapeutic target for age-associated neurodegeneration.

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 Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway

2021 ◽  
Vol 15 ◽  
Author(s):  
Eduard Bentea ◽  
Laura De Pauw ◽  
Lise Verbruggen ◽  
Lila C. Winfrey ◽  
Lauren Deneyer ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Proteasome Inhibition ◽  
Cell Loss ◽  
Redox Balance ◽  
Nigrostriatal Pathway ◽  
Knock Out ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Nigrostriatal Degeneration

The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.

Abstract TP78: Combination of Neuroprotective Drug and Neural Stem Cells Benefits Aged Stroke Mice with Delayed Tissue Plasminogen Activator Treatment

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Auston Eckert ◽  
Milton H Hamblin ◽  
Jean-Pyo Lee
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Inflammatory Drug ◽  
Aged Mice ◽  
Post Stroke ◽  
Adult Mice ◽  
Tissue Plasminogen

Background: Presently, tissue plasminogen activator (tPA) is the sole FDA-approved antithrombotic treatment available for stroke. However, tPA’s harmful side effects within the central nervous system can exacerbate blood-brain barrier (BBB) damage and increase mortality. Patients should receive tPA less than 4.5 hours post-stroke. Although age alone is not an impediment for tPA treatment, the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We reported that intracranial transplantation of neural stem cells (hNSCs) ameliorates BBB damage caused by ischemic stroke. In this study, we examined the combined effects of minocycline (a neuroprotective and anti-inflammatory drug) and hNSC transplantation on the mortality of delayed tPA-treated aged mice within 48h post-stroke. Methods and Results: We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6h post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that hNSCs (both human and mouse) transplanted into the brain 24h post-stroke rapidly improve neurological outcome in young-adult mice (4-5mo). In our current study, tPA administered within 4.5h did not increase mortality in either young-adult or aged mice. However, we found delayed tPA treatment (6h post-stroke) significantly increased the mortality of aged mice (13-18 mo) but not in young-adult mice. Here, we report that by combining minocycline prior to tPA significantly reduced mortality. Furthermore, transplanting hNSCs in minocycline-treated mice further ameliorated the pathophysiology caused by delayed tPA. Conclusions: Our findings implicate that administering the anti-apototic and anti-inflammatory drug prior to tPA injection, and then post-treating with multipotent neuroprotective hNSCs might expand the time window of tPA and reduce reperfusion injury.

scholarly journals Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

2020 ◽  
Author(s):  
Kevin W Gibbs ◽  
Chia-Chi Chuang Key ◽  
Lanazha Belfield ◽  
Jennifer Krall ◽  
Lina Purcell ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Fatty Acid ◽  
Lung Injury ◽  
Whole Body ◽  
Acid Oxidation ◽  
Aged Mice ◽  
Protein Levels ◽  
Adult Mice ◽  
Age Related ◽  
Before And After

Abstract Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.

scholarly journals Influence of Aging on the Retina and Visual Motion Processing for Optokinetic Responses in Mice

2020 ◽  
Vol 14 ◽  
Author(s):  
Yuko Sugita ◽  
Haruka Yamamoto ◽  
Yamato Maeda ◽  
Takahisa Furukawa
Keyword(s):  
Young Adult ◽  
Visual Function ◽  
Visual Motion ◽  
Late Phase ◽  
Normal Aging ◽  
Motion Processing ◽  
Adult Mice ◽  
Visual Motion Processing ◽  
Age Related ◽  
Optokinetic Responses

The decline in visual function due to normal aging impacts various aspects of our daily lives. Previous reports suggest that the aging retina exhibits mislocalization of photoreceptor terminals and reduced amplitudes of scotopic and photopic electroretinogram (ERG) responses in mice. These abnormalities are thought to contribute to age-related visual impairment; however, the extent to which visual function is impaired by aging at the organismal level is unclear. In the present study, we focus on the age-related changes of the optokinetic responses (OKRs) in visual processing. Moreover, we investigated the initial and late phases of the OKRs in young adult (2–3 months old) and aging mice (21–24 months old). The initial phase was evaluated by measuring the open-loop eye velocity of OKRs using sinusoidal grating patterns of various spatial frequencies (SFs) and moving at various temporal frequencies (TFs) for 0.5 s. The aging mice exhibited initial OKRs with a spatiotemporal frequency tuning that was slightly different from those in young adult mice. The late-phase OKRs were investigated by measuring the slow-phase velocity of the optokinetic nystagmus evoked by sinusoidal gratings of various spatiotemporal frequencies moving for 30 s. We found that optimal SF and TF in the normal aging mice are both reduced compared with those in young adult mice. In addition, we measured the OKRs of 4.1G-null (4.1G–/–) mice, in which mislocalization of photoreceptor terminals is observed even at the young adult stage. We found that the late phase OKR was significantly impaired in 4.1G–/– mice, which exhibit significantly reduced SF and TF compared with control mice. These OKR abnormalities observed in 4.1G–/– mice resemble the abnormalities found in normal aging mice. This finding suggests that these mice can be useful mouse models for studying the aging of the retinal tissue and declining visual function. Taken together, the current study demonstrates that normal aging deteriorates to visual motion processing for both the initial and late phases of OKRs. Moreover, it implies that the abnormalities of the visual function in the normal aging mice are at least partly due to mislocalization of photoreceptor synapses.

Effect of aging on tracheal mucociliary clearance in beagle dogs

1987 ◽  
Vol 62 (3) ◽  
pp. 1331-1334 ◽  
Author(s):  
S. L. Whaley ◽  
B. A. Muggenburg ◽  
F. A. Seiler ◽  
R. K. Wolff
Keyword(s):  
Young Adult ◽  
Gamma Camera ◽  
Mucociliary Clearance ◽  
Age Groups ◽  
Beagle Dogs ◽  
Velocity Measurements ◽  
Middle Aged ◽  
Age Related ◽  
Age Related Changes ◽  
Made In

Tracheal mucous velocity measurements were made in 24 beagle dogs in five age groups, using a gamma camera to detect movement of instilled 99mTc-macroaggregated albumin. Age groups were defined as immature (9–10 mo), young adult (2.8–3.0 yr), middle aged (6.7–6.9 yr), mature (9.6–9.8 yr), and aged dogs (13.6–16.2 yr). Mean velocities were 3.6 +/- 0.4 (SE) mm/min in the immature dogs, 9.7 +/- 0.6 mm/min in the young adults, 6.9 +/- 0.5 mm/min in the middle-aged dogs, 3.5 +/- 0.8 mm/min in the mature dogs, and 2.9 +/- 0.5 mm/min in the aged dogs. Tracheal mucous velocity was significantly (P less than 0.05) greater in the young adult and middle-aged groups compared with the immature, mature, and aged dogs. This pattern of age-related changes was noted to be similar to age-related changes described for certain pulmonary function measurements.

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