scholarly journals α2-Antiplasmin as a potential regulator of the spatial memory process and age-related cognitive decline

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Eri Kawashita ◽  
Keiichi Ishihara ◽  
Haruko Miyaji ◽  
Yu Tanishima ◽  
Akiko Kiriyama ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spatial Memory ◽  
Cognitive Decline ◽  
Brain Aging ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Negative Regulator ◽  
Memory Process ◽  
Age Related ◽  
Brain Oxidative Stress

Abstract α2-Antiplasmin (α2AP), a principal physiological plasmin inhibitor, is mainly produced by the liver and kidneys, but it is also expressed in several parts of the brain, including the hippocampus and cerebral cortex. Our previous study demonstrated that α2AP knockout mice exhibit spatial memory impairment in comparison to wild-type mice, suggesting that α2AP is necessary for the fetal and/or neonatal development of the neural network for spatial memory. However, it is still unclear whether α2AP plays a role in the memory process. The present study demonstrated that adult hippocampal neurogenesis and remote spatial memory were enhanced by the injection of an anti-α2AP neutralizing antibody in WT mice, while the injection of α2AP reduced hippocampal neurogenesis and impaired remote spatial memory, suggesting that α2AP is a negative regulator in memory processing. The present study also found that the levels of α2AP in the brains of old mice were higher than those in young mice, and a negative correlation between the α2AP level and spatial working memory. In addition, aging-dependent brain oxidative stress and hippocampal inflammation were attenuated by α2AP deficiency. Thus, an age-related increase in α2AP might cause cognitive decline accompanied by brain oxidative stress and neuroinflammation. Taken together, our findings suggest that α2AP is a key regulator of the spatial memory process, and that it may represent a promising target to effectively regulate healthy brain aging.

scholarly journals Epigenetic rejuvenation of the hippocampus by environmental enrichment

2019 ◽  
Author(s):  
Sara Zocher ◽  
Rupert W. Overall ◽  
Mathias Lesche ◽  
Andreas Dahl ◽  
Gerd Kempermann
Keyword(s):  
Dna Methylation ◽  
Brain Function ◽  
Environmental Enrichment ◽  
Brain Aging ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Lifestyle Interventions ◽  
Epigenetic Changes ◽  
Aging Effects ◽  
Age Related

AbstractThe decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that environmental enrichment counteracted age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is known to control neuronal functions. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.

scholarly journals Polyphenol-rich extract from grape and blueberry attenuates cognitive decline and improves neuronal function in aged mice

2018 ◽  
Vol 7 ◽  
Author(s):  
Julien Bensalem ◽  
Stéphanie Dudonné ◽  
David Gaudout ◽  
Laure Servant ◽  
Frédéric Calon ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Learning And Memory ◽  
High Performance ◽  
Brain Plasticity ◽  
Memory Deficits ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Native Form ◽  
Age Related ◽  
The Brain

AbstractAgeing is characterised by memory deficits, associated with brain plasticity impairment. Polyphenols from berries, such as flavan-3-ols, anthocyanins, and resveratrol, have been suggested to modulate synaptic plasticity and cognitive processes. In the present study we assessed the preventive effect of a polyphenol-rich extract from grape and blueberry (PEGB), with high concentrations of flavonoids, on age-related cognitive decline in mice. Adult and aged (6 weeks and 16 months) mice were fed a PEGB-enriched diet for 14 weeks. Learning and memory were assessed using the novel object recognition and Morris water maze tasks. Brain polyphenol content was evaluated with ultra-high-performance LC-MS/MS. Hippocampal neurotrophin expression was measured using quantitative real-time PCR. Finally, the effect of PEGB on adult hippocampal neurogenesis was assessed by immunochemistry, counting the number of cells expressing doublecortin and the proportion of cells with dendritic prolongations. The combination of grape and blueberry polyphenols prevented age-induced learning and memory deficits. Moreover, it increased hippocampal nerve growth factor (Ngf) mRNA expression. Aged supplemented mice displayed a greater proportion of newly generated neurons with prolongations than control age-matched mice. Some of the polyphenols included in the extract were detected in the brain in the native form or as metabolites. Aged supplemented mice also displayed a better survival rate. These data suggest that PEGB may prevent age-induced cognitive decline. Possible mechanisms of action include a modulation of brain plasticity. Post-treatment detection of phenolic compounds in the brain suggests that polyphenols may act directly at the central level, while they can make an impact on mouse survival through a potential systemic effect.

scholarly journals Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

2021 ◽  
Vol 7 (21) ◽  
pp. eabe4601
Author(s):  
Sandro Da Mesquita ◽  
Jasmin Herz ◽  
Morgan Wall ◽  
Taitea Dykstra ◽  
Kalil Alves de Lima ◽  
...  
Keyword(s):  
T Cells ◽  
Cognitive Decline ◽  
Brain Aging ◽  
Therapeutic Potential ◽  
T Cell Response ◽  
Age Related ◽  
Lymphatic Vasculature ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

The Antioxidant Resveratrol from Polygonum Cuspidatum Reverses Memory Impairment and Brain Oxidative Stress in SAMP8 Mice

2011 ◽  
Vol 422 ◽  
pp. 470-473
Author(s):  
Gui Shan Liu ◽  
Ze Sheng Zhang ◽  
Bo Yang ◽  
Wei He
Keyword(s):  
Oxidative Stress ◽  
Learning And Memory ◽  
Open Field ◽  
Field Test ◽  
Memory Impairment ◽  
Open Field Test ◽  
Pharmacological Action ◽  
Age Related ◽  
Brain Oxidative Stress ◽  
Samp8 Mice

Resveratrol (RVT) is a phytoalexin polyphenolic compound found in various plants, including grapes, berries and peanuts. Recently, studies have documented various health benefits of resveratrol including cardiovascular and cancer-chemopreventive properties. The aim of the present study was to demonstrate the effects of resveratrol on the learning and memory impairment. The senescence-accelerated mice (SAM) were introgastric gavage administrated resveratrol (25,100mg/(kg•bw)) for 60 days. The learning and memory behavior was assessed using open-field test while the parameters of oxidative stress assessed were malondialdehyde (MDA) and superoxide dismutases (SOD).The results showed that resveratrol significantly improved the learning and memory ability in open-field test. Further investigation showed that resveratrol restored SOD levels, but decreased MDA level in the mouce brain. These results indicated that the pharmacological action of RVT may offer a novel therapeutic strategy for the treatment of age-related conditions.

Aging

2019 ◽  
pp. 105-112
Author(s):  
Risto Näätänen ◽  
Teija Kujala ◽  
Gregory Light
Keyword(s):  
Hearing Loss ◽  
Speech Perception ◽  
Cognitive Decline ◽  
Temporal Processing ◽  
Brain Aging ◽  
Brain Plasticity ◽  
Part Of Speech ◽  
Memory Traces ◽  
Age Related ◽  
The Brain

This chapter shows that MMN and its magnetoencephalographic (MEG) equivalent MMNm are sensitive indices of aging-related perceptual and cognitive decline. Importantly, the age-related neural changes are associated with a decrease of general brain plasticity, i.e. that of the ability of the brain to form and maintain sensory-memory traces, a necessary basis for veridical perception and appropriate cognitive brain function. MMN/MMNm to change in stimulus duration is particularly affected by aging, suggesting the increased vulnerability of temporal processing to brain aging and accounting, for instance, for a large part of speech-perception difficulties of the aged beyond the age-related peripheral hearing loss.

scholarly journals The Effects of Gene-Environment Interactions Between Cadmium Exposure and Apolipoprotein E4 on Memory in a Mouse Model of Alzheimer’s Disease

2019 ◽  
Author(s):  
Liang Zhang ◽  
Hao Wang ◽  
Glen M Abel ◽  
Daniel R Storm ◽  
Zhengui Xia
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Health Concern ◽  
Apoe Ε4 ◽  
Gene Environment ◽  
Cd Exposure

Abstract Cadmium (Cd) is a heavy metal of great public health concern. Recent studies suggested a link between Cd exposure and cognitive decline in humans. The ε4 allele, compared with the common ε3 allele, of the human apolipoprotein E gene (ApoE) is associated with accelerated cognitive decline and increased risks for Alzheimer’s disease (AD). To investigate the gene-environment interactions (GxE) between ApoE-ε4 and Cd exposure on cognition, we used a mouse model of AD that expresses human ApoE-ε3 (ApoE3-KI [knock-in]) or ApoE-ε4 (ApoE4-KI). Mice were exposed to 0.6 mg/l CdCl2 through drinking water for 14 weeks and assessed for hippocampus-dependent memory. A separate cohort was sacrificed immediately after exposure and used for Cd measurements and immunostaining. The peak blood Cd was 0.3–0.4 µg/l, within levels found in the U.S. general population. All Cd-treated animals exhibited spatial working memory deficits in the novel object location test. This deficit manifested earlier in ApoE4-KI mice than in ApoE3-KI within the same sex and earlier in males than females within the same genotype. ApoE4-KI but not ApoE3-KI mice exhibited reduced spontaneous alternation later in life in the T-maze test. Finally, Cd exposure impaired neuronal differentiation of adult-born neurons in the hippocampus of male ApoE4-KI mice. These data suggest that a GxE between ApoE4 and Cd exposure leads to accelerated cognitive impairment and that impaired adult hippocampal neurogenesis may be one of the underlying mechanisms. Furthermore, male mice were more susceptible than female mice to this GxE effect when animals were young.

scholarly journals Thioredoxin Binding Protein-2 Regulates Autophagy of Human Lens Epithelial Cells under Oxidative Stress via Inhibition of Akt Phosphorylation

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Jiaojie Zhou ◽  
Ke Yao ◽  
Yidong Zhang ◽  
Guangdi Chen ◽  
Kairan Lai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Cell Viability ◽  
Binding Protein ◽  
Negative Regulator ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Human Lens Epithelial Cells ◽  
Age Related

Oxidative stress plays an essential role in the development of age-related cataract. Thioredoxin binding protein-2 (TBP-2) is a negative regulator of thioredoxin (Trx), which deteriorates cellular antioxidant system. Our study focused on the autophagy-regulating effect of TBP-2 under oxidative stress in human lens epithelial cells (LECs). Human lens epithelial cells were used for cell culture and treatment. Lentiviral-based transfection system was used for overexpression of TBP-2. Cytotoxicity assay, western blot analysis, GFP/mCherry-fused LC3 plasmid, immunofluorescence, and transmission electronic microscopy were performed. The results showed that autophagic response of LECs with increased LC3-II, p62, and GFP/mCherry-LC3 puncta (P<0.01) was induced by oxidative stress. Overexpression of TBP-2 further strengthens this response and worsens the cell viability (P<0.01). Knockdown of TBP-2 attenuates the autophagic response and cell viability loss induced by oxidative stress. TBP-2 mainly regulates autophagy in the initiation stage, which is mTOR-independent and probably caused by the dephosphorylation of Akt under oxidative stress. These findings suggest a novel role of TBP-2 in human LECs under oxidative stress. Oxidative stress can cause cell injury and autophagy in LECs, and TBP-2 regulates this response. Hence, this study provides evidence regarding the role of TBP-2 in lens and the possible mechanism of cataract development.

scholarly journals Telomere length and human hippocampal neurogenesis

2020 ◽  
Vol 45 (13) ◽  
pp. 2239-2247 ◽  
Author(s):  
Alish B. Palmos ◽  
Rodrigo R. R. Duarte ◽  
Demelza M. Smeeth ◽  
Erin C. Hedges ◽  
Douglas F. Nixon ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Psychiatric Disorder ◽  
Telomere Length ◽  
Gene Networks ◽  
Hippocampal Neurogenesis ◽  
Telomere Maintenance ◽  
Adult Hippocampal Neurogenesis ◽  
Telomere Shortening ◽  
Age Related

Abstract Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10−5), and risk for schizophrenia (P ≤ 1 × 10−10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.

scholarly journals Nutrients, Microglia Aging, and Brain Aging

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Zhou Wu ◽  
Janchun Yu ◽  
Aiqin Zhu ◽  
Hiroshi Nakanishi
Keyword(s):  
Oxidative Stress ◽  
Cognitive Decline ◽  
Systemic Inflammation ◽  
Brain Aging ◽  
Oxygen Species ◽  
Cellular Activation ◽  
Proinflammatory Mediators ◽  
The World ◽  
Age Dependent ◽  
The Brain

As the life expectancy continues to increase, the cognitive decline associated with Alzheimer’s disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of “microglia aging.” This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

scholarly journals The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

2020 ◽  
Vol 29 (12) ◽  
pp. 1950-1968
Author(s):  
Charlotte Castillon ◽  
Laurine Gonzalez ◽  
Florence Domenichini ◽  
Sandrine Guyon ◽  
Kevin Da Silva ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Spatial Memory ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
Memory Task ◽  
Clinical Signs ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

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