Differences in lipidome and metabolome organization of prefrontal cortex among human populations

AbstractHuman populations, despite their overwhelming similarity, contain some distinct phenotypic, genetic, epigenetic, and gene expression features. In this study, we explore population differences at yet another level of molecular phenotype: the abundance of non-polar and polar low molecular weight compounds, lipids and metabolites in the prefrontal cortical region of the brain. We assessed the abundance of 1,670 lipids and 258 metabolites in 146 Han Chinese, 97 Western European, and 60 African American individuals of varying ages, covering most of the lifespan. The statistical analysis and logistic regression models both demonstrated extensive lipid and metabolic divergence of the Han Chinese individuals from the other two populations. This divergence was age-dependent, peaking in young adults, and involved metabolites and lipids clustering in specific metabolic pathways.

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Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model

Biochemical Society Transactions ◽

10.1042/bst0381001 ◽

2010 ◽

Vol 38 (4) ◽

pp. 1001-1005 ◽

Cited By ~ 14

Author(s):

Kunie Ando ◽

Karelle Leroy ◽

Céline Heraud ◽

Anna Kabova ◽

Zehra Yilmaz ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Double Mutant ◽

Transgenic Mouse Model ◽

Tau Proteins ◽

Dependent Manner ◽

Age Dependent ◽

Ad Alzheimer’S Disease ◽

Tau Aggregation ◽

The Brain

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30×TauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30×TauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.

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Comparison of age‐dependent alterations in thioredoxin 2 and thioredoxin reductase 2 expressions in hippocampi between mice and rats

Laboratory Animal Research ◽

10.1186/s42826-021-00088-y ◽

2021 ◽

Vol 37 (1) ◽

Author(s):

Yeon Ho Yoo ◽

Dae Won Kim ◽

Bai Hui Chen ◽

Hyejin Sim ◽

Bora Kim ◽

...

Keyword(s):

Thioredoxin Reductase ◽

Pyramidal Cells ◽

Brain Regions ◽

Young Age ◽

Cresyl Violet ◽

Western Blots ◽

Protein Levels ◽

Cresyl Violet Staining ◽

Age Dependent ◽

The Brain

Abstract Background Aging is one of major causes triggering neurophysiological changes in many brain substructures, including the hippocampus, which has a major role in learning and memory. Thioredoxin (Trx) is a class of small redox proteins. Among the Trx family, Trx2 plays an important role in the regulation of mitochondrial membrane potential and is controlled by TrxR2. Hitherto, age-dependent alterations in Trx2 and TrxR2 in aged hippocampi have been poorly investigated. Therefore, the aim of this study was to examine changes in Trx2 and TrxR2 in mouse and rat hippocampi by age and to compare their differences between mice and rats. Results Trx2 and TrxR2 levels using Western blots in mice were the highest at young age and gradually reduced with time, showing that no significant differences in the levels were found between the two subfields. In rats, however, their expression levels were the lowest at young age and gradually increased with time. Nevertheless, there were no differences in cellular distribution and morphology in their hippocampi when it was observed by cresyl violet staining. In addition, both Trx2 and TrxR2 immunoreactivities in the CA1-3 fields were mainly shown in pyramidal cells (principal cells), showing that their immunoreactivities were altered like changes in their protein levels. Conclusions Our current findings suggest that Trx2 and TrxR2 expressions in the brain may be different according to brain regions, age and species. Therefore, further studies are needed to examine the reasons of the differences of Trx2 and TrxR2 expressions in the hippocampus between mice and rats.

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Age-Dependent Association Between Elevated Homocysteine and Cognitive Impairment in a Post-stroke Population: A Prospective Study

Frontiers in Nutrition ◽

10.3389/fnut.2021.691837 ◽

2021 ◽

Vol 8 ◽

Author(s):

Shengnan Zhou ◽

Jiahao Chen ◽

Lin Cheng ◽

Kaili Fan ◽

Minjie Xu ◽

...

Keyword(s):

Ischemic Stroke ◽

Cognitive Impairment ◽

Multivariate Regression Analysis ◽

Logistic Regression Models ◽

Post Stroke ◽

Stroke Population ◽

Age Dependent ◽

Independent Association ◽

A Prospective Study ◽

State Examination

Background and Purpose: The results regarding the independent association between homocysteine (Hcy) levels and post-stroke cognitive impairment (PSCI) were inconsistent. The effect of age on this association has yet to be explored. This study aims to determine the relationship between Hcy levels, age, and cognitive impairment in a post-stroke population.Methods: A total of 592 patients with acute ischemic stroke (AIS) completed follow-up. Serum Hcy levels were measured enzymatically by spectrophotometry within 24 h of admission. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE) 1 month after stroke, and the scores ≤ 24 were considered as cognitive impairment. Our study was dichotomized into two groups by a cut-off of 65 years. Multivariate logistic regression models were used to determine the association between baseline Hcy levels and cognitive impairment.Results: According to the MMSE score, 317 (53.5%) patients had cognitive impairment. Patients with higher levels of Hcy were more prone to have cognitive impairment 1 month after stroke than patients with lower levels of Hcy (p < 0.001). The optimal cut-off points of Hcy level (μmol/L) were (T1) ≤ 8, (T2) 8–12, and (T3) ≥ 12. After adjusting for confounding factors, the multivariate regression analysis showed that the third Hcy tertile was independently associated with cognitive impairment [odds ratio (OR) = 2.057, 95% confidence interval (CI) = 1.133–3.735, p = 0.018). A stronger association [T2 (OR = 2.266, 95% CI = 1.042–4.926, p = 0.039); T3 (OR =3.583, 95% CI = 1.456–8.818, p = 0.005)] was found in the younger group. However, the independent association was not confirmed in the older group.Conclusions: Elevated Hcy levels in the acute phase of ischemic stroke were independently associated with cognitive impairment in a post-stroke population. Furthermore, the association was age-dependent and more meaningful in a younger population aged below 65. So, Hcy levels in patients with stroke should be well-monitored, especially in younger patients.

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Language impairments in ASD resulting from a failed domestication of the human brain

10.1101/046037 ◽

2016 ◽

Cited By ~ 1

Author(s):

Antonio Benítez-Burraco ◽

Wanda Lattanzi ◽

Elliot Murphy

Keyword(s):

Human Brain ◽

Neural Crest ◽

Language Processing ◽

Expression Profiles ◽

Autism Spectrum ◽

Human Populations ◽

Altered Expression ◽

Domestication Syndrome ◽

High Prevalence ◽

The Brain

AbstractAutism spectrum disorders (ASD) are pervasive neurodevelopmental disorders entailing social and cognitive deficits, including marked problems with language. Numerous genes have been associated with ASD, but it is unclear how language deficits arise from gene mutation or dysregulation. It is also unclear why ASD shows such high prevalence within human populations. Interestingly, the emergence of a modern faculty of language has been hypothesised to be linked to changes in the human brain/skull, but also to the process of self-domestication of the human species. It is our intention to show that people with ASD exhibit less marked domesticated traits at the morphological, physiological, and behavioural levels. We also discuss many ASD candidates represented among the genes known to be involved in the domestication syndrome (the constellation of traits exhibited by domesticated mammals, which seemingly results from the hypofunction of the neural crest) and among the set of genes involved in language function closely connected to them. Moreover, many of these genes show altered expression profiles in the brain of autists. In addition, some candidates for domestication and language-readiness show the same expression profile in people with ASD and chimps in different brain areas involved in language processing. Similarities regarding the brain oscillatory behaviour of these areas can be expected too. We conclude that ASD may represent an abnormal ontogenetic itinerary for the human faculty of language resulting in part from changes in genes important for the domestication syndrome and, ultimately, from the normal functioning of the neural crest.

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Heterogeneous model of schistosomiasis transmission and long-term control: the combined influence of spatial variation and age-dependent factors on optimal allocation of drug therapy

Parasitology ◽

10.1017/s0031182004006341 ◽

2004 ◽

Vol 130 (1) ◽

pp. 49-65 ◽

Cited By ~ 29

Author(s):

D. GURARIE ◽

C. H. KING

Keyword(s):

Large Scale ◽

Optimal Allocation ◽

Field Studies ◽

Human Populations ◽

Infection Prevalence ◽

Snail Population ◽

Extended Model ◽

Heterogeneous Model ◽

Age Dependent

Prior field studies and modelling analyses have individually highlighted the importance of age-specific and spatial heterogeneities on the risk for schistosomiasis in human populations. As long-term, large-scale drug treatment programs for schistosomiasis are initiated in subSaharan Africa and elsewhere, optimal strategies for timing and distribution of therapy have yet to be fully defined on the working, district-level scale, where strong heterogeneities are often observed among sublocations. Based on transmission estimates from recent field studies, we develop an extended model of heterogeneous schistosome transmission for distributed human and snail population clusters and age-dependent behaviour, based on a ‘mean worm burden+snail infection prevalence’ formulation. We analyse its equilibria and basic reproduction patterns and their dependence on the underlying transmission parameters. Our model allows the exploration of chemotherapy-based control strategies targeted at high-risk behavioural groups and localities, and the approach to an optimal design in terms of cost. Efficacy of the approach is demonstrated for a model environment having linked, but spatially-distributed, populations and transmission sites.

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Mutant Presenilin 2 Transgenic Mouse: Effect on an Age-Dependent Increase of Amyloid β-Protein 42 in the Brain

Journal of Neurochemistry ◽

10.1046/j.1471-4159.1998.71010313.x ◽

2002 ◽

Vol 71 (1) ◽

pp. 313-322 ◽

Cited By ~ 64

Author(s):

Fumitaka Oyama ◽

Naoya Sawamura ◽

Kimio Kobayashi ◽

Maho Morishima-Kawashima ◽

Takashi Kuramochi ◽

...

Keyword(s):

Transgenic Mouse ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Β Protein ◽

Age Dependent ◽

Presenilin 2 ◽

The Brain

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Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

Journal of Alzheimer s Disease ◽

10.3233/jad-215128 ◽

2021 ◽

pp. 1-14

Author(s):

Andrew L. Zhou ◽

Nidhi Sharda ◽

Vidur V. Sarma ◽

Kristen M. Ahlschwede ◽

Geoffry L. Curran ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Single Photon ◽

Photon Emission ◽

Amyloid Β ◽

Emission Computed Tomography ◽

Systemic Injection ◽

Age Related ◽

Age Dependent ◽

Plasma Pharmacokinetics ◽

The Brain

Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ 40, 125I-Aβ 42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ 40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ 40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

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Neuronal Replacement After Traumatic or Age-Dependent Brain Damage

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462300003755 ◽

1985 ◽

Vol 1 (1) ◽

pp. 93-107

Author(s):

Anders Björklund ◽

Fred H. Gage

Keyword(s):

Research Work ◽

Adult Rats ◽

Functional Potential ◽

Neural Grafts ◽

Age Dependent ◽

Long Time ◽

Tissue Grafts ◽

And Behavior ◽

The Brain ◽

Host Brain

During the last few years evidence has accumulated that fetal neurons, implanted into the depth of the brain in adult rats, can reestablish damaged connections in the host brain and substitute functionally for elements lost or damaged as a result of a preceding lesion. This research work has led to the realization that, contrary to traditional views, the adult mammalian CNS has a potential to incorporate new neuronal elements into already established neuronal circuitry and that such implanted neurons can modify the function and behavior of the recipient. For a long time it was thought that the remarkable regenerative and functional potential of CNS tissue grafts that had been demonstrated in cold-blooded vertebrates reflected a fundamental difference in the regenerative properties of central nervous tissue between cold-blooded vertebrates and mammals. During the last few years it has become evident however, that at least certain types of intracerebral neural grafts can perfoum just as well in developing and mammals as in developing or adult submammalian vertebrates.

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Nutrients, Microglia Aging, and Brain Aging

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/7498528 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 18

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.

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