Effect of red and black ginseng on cholinergic markers, presynaptic markers, and neurotrophins in the brain of aged mice

Vascular contributions to cognitive impairment and dementia (VCID) includes multiple disorders that are identified by cognitive deficits secondary to cerebrovascular pathology. The risk of VCID is higher in people after the age of 70, and, currently, there is no effective treatment. Vascular endothelial cells (VEC) are critical components of the brain vasculature and neurovascular unit and their health is vital to the capacity of the brain vasculature to respond to stressors. However, aged VEC may enter an irreversible replicative-arrest state (senescence), which has been associated with dementia. E2F transcription factor 1 (E2F1) regulates cell cycle progression and DNA damage repair. Importantly, E2F1 deficiency is associated with cell senescence. We hypothesized that E2F1 downregulation contributes to senescence in the cerebral endothelium during aging. We used cultured primary VEC from young (4-months old, mo) and aged (18-mo) male and female mice for RNA sequencing, plasmid-based gene delivery, high-resolution microscopy, and (4-, 12-, and 18-mo) mice of the bilateral carotid artery stenosis (BCAS) model, which produces chronic cerebral hypoperfusion and recapitulates some of the features seen in patients with VCID. We found that overexpression of E2F1 reduced the levels of senescence-associated phenotypes in cultured VEC from young mice that were exposed to oxygen and glucose deprivation (p<0.001), which induces endothelial senescence. Our RNA seq data showed that the expression of E2f1 was reduced (~40%) in cultured primary VEC from aged mouse brains compared with young cells (p<0.001). E2F1 levels were reduced in the brains of aged mice. Interestingly, we found sex differences in E2F1 levels, with less protein levels (~30%) in males vs females (p<0.05), independently of age. Also, aged BCAS mice (1 month after surgery) had more severe senescence phenotypes, reduced cerebral blood flow, and worse memory deficits compared with control mice (p<0.05). The effect of BCAS was more prominent in aged mice compared with younger (4- and 12-mo) mice. In conclusion , our study identifies E2F1 as a potential regulator of endothelial senescence in mice and highlights the contribution of aging as an important factor in losing endothelial resilience.

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Effects of Long-Term Treatment with a Blend of Highly Purified Olive Secoiridoids on Cognition and Brain ATP Levels in Aged NMRI Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4070935 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Martina Reutzel ◽

Rekha Grewal ◽

Carmina Silaidos ◽

Jens Zotzel ◽

Stefan Marx ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Citrate Synthase ◽

Brain Aging ◽

Mrna Levels ◽

Nmri Mice ◽

Aged Mice ◽

Atp Levels ◽

Long Term Treatment ◽

The Brain

Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer’s disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.

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Abstract WMP45: Manipulation of the Microbiome Improves Functional Recovery After Ischemic Stroke

Stroke ◽

10.1161/str.47.suppl_1.wmp45 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Michal Jandzinski ◽

Venugopal Venna ◽

Anjali Chauhan ◽

Joerg Graf ◽

Louise D McCullough

Keyword(s):

Functional Recovery ◽

Artery Occlusion ◽

Peripheral Tissues ◽

Aged Mice ◽

Age Related ◽

Y Maze ◽

Obesity Hypertension ◽

Inflammatory Milieu ◽

Gastro Intestinal Tract ◽

The Brain

Background: Circulating inflammatory markers increase with age. This pro-inflammatory milieu makes the organism less capable of coping with stressors such as stroke. Age related inflammation occurs in both the brain and peripheral tissues like the gastro-intestinal tract. There is increasing recognition that commensal bacteria in the GI tract are altered with age or with germ-free housing, affecting the brain. The change occurs most notably in the ratio of two major phyla of the microbiome, the Firmicutes and Bacteroidetes . Young age is associated with a low ratio of the two but this ratio increases with age, which has been linked to many diseases including obesity, hypertension, and diabetes which are major risk factors for stroke. Hypothesis: We hypothesized that there would be age-related differences in the microbiome, and that restoration of a young microbiome would improve functional recovery in aged mice. Methods: Fecal transplants from young and aged donors were administered to recipient animals after suppression of endogenous microbial compositions through concentrated Streptomycin. This allowed for successful colonization of the gut with the newly transplanted microbiome. A transient middle cerebral artery occlusion (MCAO) was used in young (3-4 month) and aged (18-20 month) male mice 4 weeks after transplant. Functional recovery was assessed by neurological deficit scores, the hang wire test, and open field activity. The Y-maze was used to assess cognitive impairment. Results: We successfully reversed the microbiomes of aged organisms and gave young animals “aged” biomes. Animals with “aged” microbiomes prior to stroke had worsened functional recovery based on all behavioral tests. The “aged” biome increased mortality rates most notably in the young recipients which had over 50% mortality. Aged mice had significantly improved functional recovery as assessed by the HW test ( P < 0.05 ) and NDS after reconstitution of “young” microbiome prior to stroke compared to aged control animals with the normal “aged” microbiomes. Conclusion: Aged mice have high Firmicutes and Bacteroidetes relative abundances. Manipulation of the microbiome in young and aged mice is possible. Restoration of a youthful biome improved functional recovery in aged mice.

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Cerebral Mitochondrial Function and Cognitive Performance during Aging: A Longitudinal Study in NMRI Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4060769 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Martina Reutzel ◽

Rekha Grewal ◽

Benjamin Dilberger ◽

Carmina Silaidos ◽

Aljoscha Joppe ◽

...

Keyword(s):

Longitudinal Data ◽

Cognitive Performance ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Aging Process ◽

Brain Aging ◽

Model Organisms ◽

Nmri Mice ◽

Aged Mice ◽

The Brain

Brain aging is one of the major risk factors for the development of several neurodegenerative diseases. Therefore, mitochondrial dysfunction plays an important role in processes of both, brain aging and neurodegeneration. Aged mice including NMRI mice are established model organisms to study physiological and molecular mechanisms of brain aging. However, longitudinal data evaluated in one cohort are rare but are important to understand the aging process of the brain throughout life, especially since pathological changes early in life might pave the way to neurodegeneration in advanced age. To assess the longitudinal course of brain aging, we used a cohort of female NMRI mice and measured brain mitochondrial function, cognitive performance, and molecular markers every 6 months until mice reached the age of 24 months. Furthermore, we measured citrate synthase activity and respiration of isolated brain mitochondria. Mice at the age of three months served as young controls. At six months of age, mitochondria-related genes (complex IV, creb-1, β-AMPK, and Tfam) were significantly elevated. Brain ATP levels were significantly reduced at an age of 18 months while mitochondria respiration was already reduced in middle-aged mice which is in accordance with the monitored impairments in cognitive tests. mRNA expression of genes involved in mitochondrial biogenesis (cAMP response element-binding protein 1 (creb-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), nuclear respiratory factor-1 (Nrf-1), mitochondrial transcription factor A (Tfam), growth-associated protein 43 (GAP43), and synaptophysin 1 (SYP1)) and the antioxidative defense system (catalase (Cat) and superoxide dismutase 2 (SOD2)) was measured and showed significantly decreased expression patterns in the brain starting at an age of 18 months. BDNF expression reached, a maximum after 6 months. On the basis of longitudinal data, our results demonstrate a close connection between the age-related decline of cognitive performance, energy metabolism, and mitochondrial biogenesis during the physiological brain aging process.

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The neurotoxic actions of quinolinic acid in the central nervous system

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y86-060 ◽

1986 ◽

Vol 64 (3) ◽

pp. 369-375 ◽

Cited By ~ 29

Author(s):

S. R. El-Defrawy ◽

R. J. Boegman ◽

K. Jhamandas ◽

R. J. Beninger

Keyword(s):

Amino Acid ◽

Nmda Receptor ◽

Quinolinic Acid ◽

Excitatory Amino Acid ◽

Neuronal Degeneration ◽

Regional Distribution ◽

Nucleus Basalis ◽

Cholinergic Function ◽

The Brain ◽

Cholinergic Markers

Excitotoxins such as kainic acid, ibotenic acid, and quinolinic acid are a group of molecules structurally related to glutamate or aspartate. They are capable of exciting neurons and producing axon sparing neuronal degeneration. Quinolinic acid (QUIN), an endogenous metabolite of the amino acid, tryptophan, has been detected in brain and its concentration increases with age. The content of QUIN in the brain and the activity of the enzymes involved in its synthesis and metabolism show a regional distribution. The neuroexcitatory action of QUIN is antagonized by magnesium (Mg2+) and the aminophosphonates, proposed N-methyl-D-aspartate (NMDA) receptor antagonists, suggesting that QUIN acts at the Mg2+-sensitive NMDA receptor. Like its excitatory effects, QUIN's neurotoxic actions in the striatum are antagonized by the aminophosphonates. This suggests that QUIN neurotoxicity involves the NMDA receptor and (or) another receptor sensitive to the aminophosphonates. The neuroexcitatory and neurotoxic effects of QUIN are antagonized by kynurenic acid (KYN), another metabolite of tryptophan. QUIN toxicity is dependent on excitatory amino acid afferents and shows a regional variation in the brain. Local injection of QUIN into the nucleus basalis magnocellularis (NBM) results in a dose-dependent reduction in cortical cholinergic markers including the evoked release of acetylcholine. A significant reduction in cortical cholinergic function is maintained over a 3-month period. Coinjection of an equimolar ratio of QUIN and KYN into the NBM results in complete protection against QUIN-induced neurodegeneration and decreases in cortical cholinergic markers. In contrast, focal injections of QUIN into the frontoparietal cortex do not alter cortical cholinergic function. Animals showing central cholinergic hypofunction induced by QUIN could serve as experimental models for testing pharmacological agents aimed at improving the function of damaged cholinergic neurons.

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Striosome–dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613337113 ◽

2016 ◽

Vol 113 (40) ◽

pp. 11318-11323 ◽

Cited By ~ 56

Author(s):

Jill R. Crittenden ◽

Paul W. Tillberg ◽

Michael H. Riad ◽

Yasuyuki Shima ◽

Charles R. Gerfen ◽

...

Keyword(s):

Decision Making ◽

Connexin 43 ◽

Retrograde Tracing ◽

Nigrostriatal Pathway ◽

Related Function ◽

Human Disorders ◽

Health And Disease ◽

Cortical Regions ◽

The Brain ◽

Cholinergic Markers

The dopamine systems of the brain powerfully influence movement and motivation. We demonstrate that striatonigral fibers originating in striosomes form highly unusual bouquet-like arborizations that target bundles of ventrally extending dopamine-containing dendrites and clusters of their parent nigral cell bodies. Retrograde tracing showed that these clustered cell bodies in turn project to the striatum as part of the classic nigrostriatal pathway. Thus, these striosome–dendron formations, here termed “striosome–dendron bouquets,” likely represent subsystems with the nigro–striato–nigral loop that are affected in human disorders including Parkinson’s disease. Within the bouquets, expansion microscopy resolved many individual striosomal fibers tightly intertwined with the dopamine-containing dendrites and also with afferents labeled by glutamatergic, GABAergic, and cholinergic markers and markers for astrocytic cells and fibers and connexin 43 puncta. We suggest that the striosome–dendron bouquets form specialized integrative units within the dopamine-containing nigral system. Given evidence that striosomes receive input from cortical regions related to the control of mood and motivation and that they link functionally to reinforcement and decision-making, the striosome–dendron bouquets could be critical to dopamine-related function in health and disease.

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Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

10.21203/rs.2.21718/v1 ◽

2020 ◽

Author(s):

Maria Pilar Blasco ◽

Anjali Chauhan ◽

Pedram Honarpisheh ◽

Hilda Ahnstedt ◽

John d’Aigle ◽

...

Keyword(s):

Ischemic Stroke ◽

Mast Cells ◽

Receptor Expression ◽

Mast Cell Activation ◽

Low Grade ◽

Gut Inflammation ◽

Aged Mice ◽

Post Stroke ◽

Age Related ◽

The Brain

Abstract Background Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation and mast cells residing in the gut are a primary source of histamine. Methods Stroke was induced in male C57BL/6J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice, mice underwent MCAO surgery and were euthanized at 6h, 24h and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice was associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. Results We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of mast cells and histamine receptors in the gut. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24 hours post-stroke. Conclusion An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

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Aging-dependent downregulation of SUV39H1 histone methyltransferase increases susceptibility to stress-induced depressive behavior

10.21203/rs.3.rs-526053/v1 ◽

2021 ◽

Author(s):

Jung-Eun Lee ◽

So-Young Park ◽

Pyung-Lim Han

Keyword(s):

Chromatin Immunoprecipitation ◽

Underlying Mechanism ◽

Histone Methyltransferase ◽

Bdnf Expression ◽

Ht22 Cells ◽

Depressive Behavior ◽

Aged Mice ◽

Gene Expression Alteration ◽

Induced Changes ◽

The Brain

Abstract Aging induces cellular and molecular changes including gene expression alteration in the brain, which might be associated with aging-dependent increase in vulnerability to stress-induced depression. However, the underlying mechanism is not clearly understood. In the present study, we investigate how aging changes the ability to cope with stress and increases sensitivity to stress. Aged mice have decreased expression of SUV39H1 histone methyltransferase and increased expression of Mkp-1 in the hippocampus. The siRNA-mediated knockdown of SUV39H1 increases Mkp-1 expression and suppresses p-CREB and Bdnf expression in HT22 cells and in the hippocampus of mice. Chromatin immunoprecipitation assays indicate that the levels of SUV39H1 and methylated histone-H3 bound to the promoter of the Mkp-1 in the hippocampus are reduced in aged mice. Aged mice exhibit depression-like behavior following weak stress that does not induce depressive behavior in young mice. Rosmarinic acid, a phenolic compound that increases SUV39H1 expression, reverses stress-induced changes of SUV39H1, Mkp-1, and Bdnf expression in the hippocampus via an overlapping but distinct mechanism from those of fluoxetine and imipramine and produces anti-depressive effects. These results suggest that aging increases susceptibility to stress via downregulation of SUV39H1 and changes in SUV39H1-regulated signaling pathways in the hippocampus.

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Targeting VCAM1 rejuvenates the brain in aged mice

Nature Reviews Immunology ◽

10.1038/s41577-019-0183-y ◽

2019 ◽

Vol 19 (7) ◽

pp. 415-415

Author(s):

Yvonne Bordon

Keyword(s):

Aged Mice ◽

The Brain

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A Walnut-Enriched Diet Modifies the Oxylipin Profile in Liver and Brain of Aged Mice — Impact on Inflammation Markers

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_019 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1203-1203

Author(s):

Gunter Eckert ◽

Gunter Esselun ◽

Elisabeth Koch ◽

Nils Schebb

Keyword(s):

Physical Activity ◽

Fatty Acids ◽

Brain Aging ◽

Inflammatory Marker ◽

Inflammation Markers ◽

Aged Mice ◽

Funding Sources ◽

Age Related ◽

The Brain ◽

Related Increase

Abstract Objectives Neuroinflammation contributes to brain-aging which may be mitigated by anti-inflammatory oxylipins. Based on our previous findings that a 6% walnut-enriched diet alone, and additional physical activity (PA), enhanced cognition in 18 months old NMRI, we now investigated the effects of this diet on oxylipin- and inflammatory marker levels in liver and brain. Methods 18 months and 3 months old female NMRI mice were fed with a 6% walnut-enriched diet. Oxylipins were determined in brain and liver sections using LC-MS. Expression of IL1β gene was determined by qRT-PCR. Results The walnut diet compensates for the age related increase in IL1β gene expression in the liver of mice, whereas expression in the brain was not affected. Basal levels of oxylipins in brain and liver samples isolated from young mice were generally lower compared to aged mice. The walnut diet further increased oxylipin levels of walnut specific fatty acids in liver and brain of aged mice. Enrichment of linoleic acid (LA) and α-linolenic acid (ALA) derived oxylipin levels were quantitatively higher in the liver compared to the brain (P < 0.0001). Hydroxy-oxylipins (HO) based on fatty acid LA were significantly increased in brain (P < 0.001) and liver (P < 0.0001) compared to control mice, while ALA based HO were only detected in the brains of walnut fed mice. The walnut diet in combination with physical activity (PA) reduced ARA based oxylipin levels (P < 0.05). Across all groups, concentrations of prostanoids were higher in the brain as compared to liver (P < 0.001). In the liver, walnuts tended to decrease PGD2 and TxB2 levels while increasing 6-keto PGF1α. The latter, as well as TxB2 tended to be decreased in the brain. Other ARA based prostanoids were unaffected. Effects of PA were contrary to each other, tending to increase ARA based prostanoids in the liver while decreasing them in the brain. PA further enhanced this effect in the brain, but tended to increase the inflammatory response in the liver. Conclusions A walnut diet differentially affects the oxylipin profile of liver and brain in aged mice. Production of oxylipins based on walnut fatty acids is generally increased. Attenuation of age-related, chronic inflammation in might be one of walnut's benefits and may contribute to a healthier aging of the brain. Funding Sources Research was supported by grants from California Walnut Commission.

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