Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline

The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.

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The Astrogenic Balance in the Aging Brain

Current Neuropharmacology ◽

10.2174/1570159x19666210420095118 ◽

2021 ◽

Vol 19 ◽

Author(s):

Fotis Andromidas ◽

Saeid Atashpanjeh ◽

Abigail J. Myers ◽

Brooke E. MacKinnon ◽

Melanie M. Shaffer ◽

...

Keyword(s):

Cell Cycle ◽

Transcription Factors ◽

Neurodegenerative Disease ◽

Inverse Correlation ◽

The Elderly ◽

Synaptic Function ◽

Aging Brain ◽

Therapeutic Approaches ◽

Disease States ◽

Prevalence Of Cancer

: An inverse correlation between the incidence of cancer and neurodegenerative disease has been observed, with the prevalence of cancer peaking around 60 years of age, then slowly tapering off as neurodegenerative diseases increase in the elderly. Although the diseases rarely occur concurrently, the same genes are differentially expressed between the diseases, with four transcription factors found to be in common for their expression. In the brain, mature astrocytes are the origin of astrocytoma, which make up 58.2% of malignant brain tumors in patients 65 or older, while GFAP+ astrocyte-like neural stem cells from the subventricular zone give rise to glioblastoma and anaplastic astrocytoma, which make up 41.6%. Likewise, in neurodegenerative disease, a decrease in astrocyte density is observed in early disease states, and senescent astrocytes increase. Because astrocytes coordinate synaptic function, astrocyte dysfunction likely contributes to or causes initial synapse loss and cognitive decline seen in neurodegenerative disease. In non-disease states, astrocytes retain their ability to successfully re-enter the cell cycle through adult astrogenesis to maintain the neuroenvironment, and controlled astrocytic proliferation could be an important contributor to neurological function. Disruption to this astrogenic balance could account for the inverse correlation of cell cycle dysregulation resulting in malignant astrocytes and tumorigenesis, and astrocytic senescence and cell death without self-renewal in aging resulting in neurodegenerative disease. The current understanding of the astrocytic roles of the transcription factors that could be the cause of this imbalance will be discussed, as well as possible therapeutic approaches to modulate their expression in the astrocyte.

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Robotics in Surgical Techniques Robotics in Surgical Techniques

Rapid Automation ◽

10.4018/978-1-5225-8060-7.ch072 ◽

2019 ◽

pp. 1528-1542

Author(s):

Vassilia Costarides ◽

Apollon Zygomalas ◽

Kostas Giokas ◽

Dimitris Koutsouris

Keyword(s):

Large Scale ◽

Surgical Techniques ◽

Interdisciplinary Approach ◽

The Elderly ◽

Cellular Level ◽

Exciting Field ◽

Technological Advances ◽

Quality Of Life Indicators ◽

The Disabled ◽

Robotic Devices

Healthcare robotic applications are a growing trend due to rapid demographic changes that affect healthcare systems, professionals and quality of life indicators, for the elderly, the injured and the disabled. Current technological advances in robotic systems offer an exciting field for medical research, as the interdisciplinary approach of robotics in healthcare and specifically in surgery is continuously gaining ground. This chapter features a review of current applications, from external large scale robotic devices to nanoscale swarm robots programmed to interact on a cellular level.

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Robotics in Surgical Techniques Robotics in Surgical Techniques

Data Analytics in Medicine ◽

10.4018/978-1-7998-1204-3.ch102 ◽

2020 ◽

pp. 2033-2047

Author(s):

Vassilia Costarides ◽

Apollon Zygomalas ◽

Kostas Giokas ◽

Dimitris Koutsouris

Keyword(s):

Large Scale ◽

Surgical Techniques ◽

Interdisciplinary Approach ◽

The Elderly ◽

Cellular Level ◽

Exciting Field ◽

Technological Advances ◽

Quality Of Life Indicators ◽

The Disabled ◽

Robotic Devices

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Neuropathological findings in entorhinal cortex of subjects aged 50 years or older and their correlation with dementia in a sample from Southern Brazil

Dementia & Neuropsychologia ◽

10.1590/1980-57642016dn11-010005 ◽

2017 ◽

Vol 11 (1) ◽

pp. 24-31 ◽

Cited By ~ 1

Author(s):

Edson Rodrigues Neto ◽

Mariana K. Fonseca ◽

Álvaro C.B. Guedes ◽

Francine H. Oliveira ◽

Arlete Hilbig ◽

...

Keyword(s):

Entorhinal Cortex ◽

Beta Amyloid ◽

The Elderly ◽

Single Type ◽

Aging Brain ◽

Amyloid Protein ◽

Brain Pathology ◽

Protein Deposits ◽

Common Association ◽

Neuropathological Criteria

ABSTRACT Introduction: The aims of this study were to survey neurodegenerative changes detected by abnormal protein deposits in the Entorhinal Cortex (EC) of subjects aged 50 years or older and to correlate these findings with suspected dementia, as detected by the IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly) . Methods: Fourteen brains were submitted to the immunohistochemistry technique for different proteins (beta-amyloid, tau, -synuclein and phospho-TDP-43) and data obtained compared with IQCODE scores. Results: Fifty-seven percent of the individuals exhibited IQCODE results compatible with dementia, being classified into the demented group (DG): 87.5% of patients had neuropathological findings corresponding to Alzheimer's-like brain pathology (ALBP). Of the patients in the non-demented group (NDG), 16.7% met neuropathological criteria for ALBP. All individuals in the DG showed deposits of more than one kind of protein in the EC. The most common association was hyperphosphorylated tau and beta-amyloid protein (87.5%). Discussion: Most individuals with dementia had neuropathological findings of ALBP, as did one individual with no signs of dementia, characterizing a preclinical stage. The results of this study suggest that deposits of a single type of anomalous protein are normal findings in an aging brain, while more than one kind of protein or the combined presence of anomalous protein deposits indicate the presence of dementia.

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Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21207777 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7777 ◽

Cited By ~ 2

Author(s):

Luca Colucci-D’Amato ◽

Luisa Speranza ◽

Floriana Volpicelli

Keyword(s):

Adult Neurogenesis ◽

Neurotrophic Factor ◽

Protective Factor ◽

Therapeutic Potential ◽

Synaptic Activity ◽

Neurotrophin Receptor ◽

Mammalian Brain ◽

P75 Neurotrophin Receptor ◽

Spine Density ◽

The Central Nervous System

Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively studied neurotrophins in the mammalian brain. BDNF signals through the tropomycin receptor kinase B (TrkB) and the low affinity p75 neurotrophin receptor (p75NTR). BDNF plays an important role in proper growth, development, and plasticity of glutamatergic and GABAergic synapses and through modulation of neuronal differentiation, it influences serotonergic and dopaminergic neurotransmission. BDNF acts as paracrine and autocrine factor, on both pre-synaptic and post-synaptic target sites. It is crucial in the transformation of synaptic activity into long-term synaptic memories. BDNF is considered an instructive mediator of functional and structural plasticity in the central nervous system (CNS), influencing dendritic spines and, at least in the hippocampus, the adult neurogenesis. Changes in the rate of adult neurogenesis and in spine density can influence several forms of learning and memory and can contribute to depression-like behaviors. The possible roles of BDNF in neuronal plasticity highlighted in this review focus on the effect of antidepressant therapies on BDNF-mediated plasticity. Moreover, we will review data that illustrate the role of BDNF as a potent protective factor that is able to confer protection against neurodegeneration, in particular in Alzheimer’s disease. Finally, we will give evidence of how the involvement of BDNF in the pathogenesis of brain glioblastoma has emerged, thus opening new avenues for the treatment of this deadly cancer.

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Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain

Neuron ◽

10.1016/j.neuron.2017.01.033 ◽

2017 ◽

Vol 93 (5) ◽

pp. 1094-1109.e7 ◽

Cited By ~ 20

Author(s):

Wei-Chao Huang ◽

Elliott Ferris ◽

Tong Cheng ◽

Cornelia Stacher Hörndli ◽

Kelly Gleason ◽

...

Keyword(s):

Genetic Architecture ◽

Cellular Level ◽

Mammalian Brain ◽

Specific Expression ◽

Allele Specific Expression ◽

Allele Specific

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Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease

Clinical Science ◽

10.1042/cs20150246 ◽

2015 ◽

Vol 129 (7) ◽

pp. 589-599 ◽

Cited By ~ 20

Author(s):

Joaquin Perez-Schindler ◽

Andrew Philp

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Nuclear Receptors ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Muscle Metabolism ◽

Cellular Level ◽

Expression Of Genes

Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease.

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Generation and Characterization of FVIII-Specific CAR-Transduced Regulatory T Cells

Blood ◽

10.1182/blood.v124.21.236.236 ◽

2014 ◽

Vol 124 (21) ◽

pp. 236-236

Author(s):

Anja Naumann ◽

Yongchan Kim ◽

Christoph Königs ◽

David W Scott

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Hemophilia A ◽

Conflicts Of Interest ◽

Therapeutic Potential ◽

Tolerance Induction ◽

Phage Display Library ◽

Therapeutic Approaches ◽

Activation Markers ◽

New Therapeutic Approaches

Abstract The development of inhibitory antibodies (inhibitors) against FVIII is the most critical complication in the treatment of hemophilia A patients as hemostasis can no longer be reestablished by FVIII replacement therapy. Immune tolerance induction by frequent FVIII infusions is demanding, costly and not successful in all treated patients leading to an urgent need for the development of new therapeutic approaches for the prevention or treatment of FVIII inhibitors. Regulatory T cells (Tregs) are important for the maintenance of tolerance and have a high therapeutic potential in the context of autoimmune or inflammatory immune disorders. As Tregs are polyclonal, treatment with Treg pools comprises the risk of a general immunosuppression. Thus, the establishment of antigen-specific Tregs could be of great benefit for a broad range of patients, including inhibitor positive hemophilia A patients. To create such specific Tregs, a FVIII-specific scFv isolated out of a synthetic phage display library was used to generate a second generation chimeric antigen receptor (CAR). To verify the specificity of the CAR for FVIII and the functionality of the recombined cytoplasmic domain (CD28 and CD3zeta), naïve CD4 T cells were retrovirally transduced with the generated CAR construct and a proliferation assay was conducted in the presence of plate-bound or soluble FVIII, as well as soluble FVIII presented by autologous irradiated PBMCs. Proliferation of transduced cells was more effective when FVIII was presented plate-bound or by PBMCs. In a therapeutically-relevant setting, this would be very promising, as transduced T cells should not be activated by soluble FVIII in the bloodstream but rather by FVIII presented on antigen-presenting cells in lymphatic organs. Next, functionality of the CAR construct in Tregs was addressed. Transduced Tregs showed extracellular expression of the scFv and could be stimulated MHC-independently with FVIII. Such stimulated cells showed increased expression of Treg activation markers LAP and GARP. Thus, by using the generated CAR for transduction of Tregs, it was possible to create FVIII-specific Tregs that can be stimulated MHC-independently, opening new possibilities for therapeutic approaches in hemophilia A patients with FVIII inhibitors. Disclosures No relevant conflicts of interest to declare.

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Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain

Neuropharmacology ◽

10.1016/j.neuropharm.2017.02.006 ◽

2017 ◽

Vol 117 ◽

pp. 182-194 ◽

Cited By ~ 34

Author(s):

Kerstin Römermann ◽

Maren Fedrowitz ◽

Philip Hampel ◽

Edith Kaczmarek ◽

Kathrin Töllner ◽

...

Keyword(s):

Blood Brain Barrier ◽

Therapeutic Potential ◽

Brain Barrier ◽

Mammalian Brain ◽

Transport Mechanisms ◽

Blood Brain ◽

Multiple Blood

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Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms221910251 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10251

Author(s):

Vladimir Sukhorukov ◽

Dmitry Voronkov ◽

Tatiana Baranich ◽

Natalia Mudzhiri ◽

Alina Magnaeva ◽

...

Keyword(s):

Glial Cells ◽

Brain Aging ◽

Cellular Level ◽

Aging Brain ◽

The Past ◽

Age Related ◽

Accumulation Of Damage ◽

Quantity Control ◽

The Brain

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.

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