scholarly journals Space-Dependent Glia–Neuron Interplay in the Hippocampus of Transgenic Models of β-Amyloid Deposition

2020 ◽  
Vol 21 (24) ◽  
pp. 9441
Author(s):  
Daniele Lana ◽  
Filippo Ugolini ◽  
Maria Grazia Giovannini
Keyword(s):  
Brain Regions ◽  
Therapeutic Strategies ◽  
Differential Sensitivity ◽  
Transgenic Models ◽  
Age Related ◽  
Neurodegenerative Pathology ◽  
Spatial Differences ◽  
Key Factor ◽  
Β Amyloid ◽  
The Brain

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer’s disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD’s histopathological hallmarks is the deposition of amyloid beta (Aβ) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies.

scholarly journals Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

2020 ◽  
Author(s):  
Thomas D. Prevot ◽  
Akiko Sumitomo ◽  
Toshifumi Tomoda ◽  
Daniel E. Knutson ◽  
Guanguan Li ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Cognitive Decline ◽  
Neuronal Morphology ◽  
Aging Brain ◽  
Primary Neuronal Culture ◽  
Efficient Treatment ◽  
Gaba A ◽  
Age Related ◽  
Β Amyloid ◽  
The Brain

ABSTRACTOver the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years. With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death. Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer’s disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.

scholarly journals Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Latarsha Porcher ◽  
Sophie Bruckmeier ◽  
Steven D. Burbano ◽  
Julie E. Finnell ◽  
Nicole Gorny ◽  
...  
Keyword(s):  
Statistical Tests ◽  
Ventral Hippocampus ◽  
Brain Regions ◽  
Cytokine Expression ◽  
Brown Norway ◽  
Mouse Strains ◽  
Gm Csf ◽  
Age Related ◽  
The Brain ◽  
Related Increase

Abstract Background Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound—particularly for interleukin 6 (IL-6)—possibly due to differences in sex, species/strain, and/or the brain regions studied. Methods As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. Results In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1β in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1β. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. Conclusions Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

scholarly journals Neuroprotective Potential of GDF11: Myth or Reality?

2019 ◽  
Vol 20 (14) ◽  
pp. 3563 ◽  
Author(s):  
Luc Rochette ◽  
Gabriel Malka
Keyword(s):  
Neurodegenerative Diseases ◽  
Blood Plasma ◽  
Neurodegenerative Disorders ◽  
Brain Aging ◽  
Therapeutic Strategies ◽  
Blood Concentrations ◽  
Age Related ◽  
Novel Therapeutic Strategies ◽  
The Brain ◽  
Novel Therapeutic

In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a “rejuvenating factor” opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies.

scholarly journals Insulin in Central Nervous System: More than Just a Peripheral Hormone

2012 ◽  
Vol 2012 ◽  
pp. 1-21 ◽  
Author(s):  
Ana I. Duarte ◽  
Paula I. Moreira ◽  
Catarina R. Oliveira
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodegenerative Disorders ◽  
Intracellular Signaling ◽  
Therapeutic Strategies ◽  
Healthy Longevity ◽  
Complex Interactions ◽  
Brain Insulin ◽  
Age Related ◽  
The Brain

Insulin signaling in central nervous system (CNS) has emerged as a novel field of research since decreased brain insulin levels and/or signaling were associated to impaired learning, memory, and age-related neurodegenerative diseases. Thus, besides its well-known role in longevity, insulin may constitute a promising therapy against diabetes- and age-related neurodegenerative disorders. More interestingly, insulin has been also faced as the potential missing link between diabetes and aging in CNS, with Alzheimer's disease (AD) considered as the “brain-type diabetes.” In fact, brain insulin has been shown to regulate both peripheral and central glucose metabolism, neurotransmission, learning, and memory and to be neuroprotective. And a future challenge will be to unravel the complex interactions between aging and diabetes, which, we believe, will allow the development of efficient preventive and therapeutic strategies to overcome age-related diseases and to prolong human “healthy” longevity. Herewith, we aim to integrate the metabolic, neuromodulatory, and neuroprotective roles of insulin in two age-related pathologies: diabetes and AD, both in terms of intracellular signaling and potential therapeutic approach.

scholarly journals Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 375
Author(s):  
Inês C. Brás ◽  
Tiago F. Outeiro
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Cell Protein ◽  
Protein Assemblies ◽  
Lewy Pathology ◽  
Tremendous Progress ◽  
The Brain ◽  
Made In

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

scholarly journals Neuroscience Research on Human Visual Path Integration: Empirical Overview and Strategic Considerations

2021 ◽  
Author(s):  
Jimmy Y. Zhong
Keyword(s):  
Path Integration ◽  
Hippocampal Formation ◽  
Brain Activity ◽  
Brain Regions ◽  
Neural Basis ◽  
Age Related ◽  
Neuroscience Research ◽  
Integration Strategies ◽  
The Impact ◽  
The Brain

Over the past two decades, many neuroimaging studies have attempted uncover the brain regions and networks involved in path integration and identify the underlying neurocognitive mechanisms. Although these studies made inroads into the neural basis of path integration, they have yet to offer a full disclosure of the functional specialization of the brain regions supporting path integration. In this paper, I reviewed notable neuroscientific studies on visual path integration in humans, identified the commonalities and discrepancies in their findings, and incorporated fresh insights from recent path integration studies. Specifically, this paper presented neuroscientific studies performed with virtual renditions of the triangle/path completion task and addressed whether or not the hippocampus is necessary for human path integration. Based on studies that showed evidence supporting and negating the involvement of the hippocampal formation in path integration, this paper introduces the proposal that the use of different path integration strategies may determine the extent to which the hippocampus and entorhinal cortex are engaged during path integration. To this end, recent studies that investigated the impact of different path integration strategies on behavioral performance and functional brain activity were discussed. Methodological concerns were raised with feasible recommendations for improving the experimental design of future strategy-related path integration studies, which can cover cognitive neuroscience research on age-related differences in the role of the hippocampal formation in path integration and Bayesian modelling of the interaction between landmark and self-motion cues. The practical value of investigating different path integration strategies was also discussed briefly from a biomedical perspective.

scholarly journals Probabilistic Critical Controllability Analysis of Protein Interaction Networks Integrating Normal Brain Ageing Gene Expression Profiles

2021 ◽  
Vol 22 (18) ◽  
pp. 9891
Author(s):  
Eimi Yamaguchi ◽  
Tatsuya Akutsu ◽  
Jose C. Nacher
Keyword(s):  
Gene Expression ◽  
Biological Networks ◽  
Expression Profiles ◽  
Dominating Set ◽  
Gene Expression Profiles ◽  
Brain Regions ◽  
Normal Brain ◽  
Age Related ◽  
Brain Ageing ◽  
The Brain

Recently, network controllability studies have proposed several frameworks for the control of large complex biological networks using a small number of life molecules. However, age-related changes in the brain have not been investigated from a controllability perspective. In this study, we compiled the gene expression profiles of four normal brain regions from individuals aged 20–99 years and generated dynamic probabilistic protein networks across their lifespan. We developed a new algorithm that efficiently identified critical proteins in probabilistic complex networks, in the context of a minimum dominating set controllability model. The results showed that the identified critical proteins were significantly enriched with well-known ageing genes collected from the GenAge database. In particular, the enrichment observed in replicative and premature senescence biological processes with critical proteins for male samples in the hippocampal region led to the identification of possible new ageing gene candidates.

scholarly journals Age-related declines in neural distinctiveness correlate across brain areas and result from both decreased reliability and increased confusability

2021 ◽  
Author(s):  
Molly Simmonite ◽  
Thad A Polk
Keyword(s):  
Neural Activity ◽  
Healthy Aging ◽  
Brain Regions ◽  
Aging Brain ◽  
Activation Patterns ◽  
Neural Representations ◽  
Age Related ◽  
Behavioural Performance ◽  
The Difference ◽  
The Brain

According to the neural dedifferentiation hypothesis, age-related reductions in the distinctiveness of neural representations contribute to sensory, cognitive, and motor declines associated with aging: neural activity associated with different stimulus categories becomes more confusable with age and behavioural performance suffers as a result. Initial studies investigated age-related dedifferentiation in the visual cortex, but subsequent research has revealed declines in other brain regions, suggesting that dedifferentiation may be a general feature of the aging brain. In the present study, we used functional magnetic resonance imaging to investigate age-related dedifferentiation in the visual, auditory, and motor cortices. Participants were 58 young adults and 79 older adults. The similarity of activation patterns across different blocks of the same condition was calculated (within-condition correlation, a measure of reliability) as was the similarity of activation patterns elicited by different conditions (between-category correlations, a measure of confusability). Neural distinctiveness was defined as the difference between the mean within- and between-condition similarity. We found age-related reductions in neural distinctiveness in the visual, auditory, and motor cortices, which were driven by both decreases in within-category similarity and increases in between-category similarity. There were significant positive cross-region correlations between neural distinctiveness in different regions. These correlations were driven by within-category similarities, a finding that indicates that declines in the reliability of neural activity appear to occur in tandem across the brain. These findings suggest that the changes in neural distinctiveness that occur in healthy aging result from changes in both the reliability and confusability of patterns of neural activity.

scholarly journals Adolescent tuning of association cortex in human structural brain networks

2017 ◽  
Author(s):  
František Váša ◽  
Jakob Seidlitz ◽  
Rafael Romero-Garcia ◽  
Kirstie J. Whitaker ◽  
Gideon Rosenthal ◽  
...  
Keyword(s):  
Sharp Decrease ◽  
Brain Regions ◽  
Brain Network ◽  
Association Cortex ◽  
Structural Correlation ◽  
Age Related ◽  
Cortical Regions ◽  
Structural Networks ◽  
The Brain ◽  
Age Related Changes

AbstractMotivated by prior data on local cortical shrinkage and intracortical myelination, we predicted age-related changes in topological organisation of cortical structural networks during adolescence. We estimated structural correlation from magnetic resonance imaging measures of cortical thickness at 308 regions in a sample of N=297 healthy participants, aged 14-24 years. We used a novel sliding-window analysis to measure age-related changes in network attributes globally, locally and in the context of several community partitions of the network. We found that the strength of structural correlation generally decreased as a function of age. Association cortical regions demonstrated a sharp decrease in nodal degree (hubness) from 14 years, reaching a minimum at approximately 19 years, and then levelling off or even slightly increasing until 24 years. Greater and more prolonged age-related changes in degree of cortical regions within the brain network were associated with faster rates of adolescent cortical myelination and shrinkage. The brain regions that demonstrated the greatest age-related changes were concentrated within prefrontal modules. We conclude that human adolescence is associated with biologically plausible changes in structural imaging markers of brain network organization, consistent with the concept of tuning or consolidating anatomical connectivity between frontal cortex and the rest of the connectome.

scholarly journals Perspective of application of nonlinear stimulation therapy in the treatment of traumatic brain injuries and maintenance of cognitive functions in the elderly

2018 ◽  
pp. 36-43 ◽  
Author(s):  
M. V. Zueva
Keyword(s):  
Cognitive Decline ◽  
Brain Injuries ◽  
The Elderly ◽  
Traumatic Brain Injuries ◽  
Sensory Stimuli ◽  
Optical Signals ◽  
Age Related ◽  
Neurodegenerative Pathology ◽  
The Brain ◽  
Stimulation Of

Cognitive decline characterizes normal physiological aging and is aggravated by the development of age-related neurodegenerative pathology and traumatic brain damage (TBI). Te review analyzes widely discussed in the scientifc literature non-drug methods of rehabilitation of patients with TBI and elderly people suffering from cognitive decline, including the paradigm of enrichment of the environment, cognitive and physical training and various types of stimulation therapy and their shortcomings. Special attention is paid to the advantages of fractal stimulation of the brain by complex-structured optical signals and sensory stimuli of another modality. It is assumed that the use of new approaches to neurorehabilitation, which increase the potential of neuroplasticity will also allow strengthening the therapeutic and learning impacts of any other methods of training and treating the brain.

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