scholarly journals Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

2022 ◽  
Vol 23 (2) ◽  
pp. 629
Author(s):  
Xiangli Zhao ◽  
Sadaf Hasan ◽  
Benjamin Liou ◽  
Yi Lin ◽  
Ying Sun ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Brain Tissue ◽  
Clinical Settings ◽  
Progressive Degeneration ◽  
Disease Modifying Therapies ◽  
Β Amyloid ◽  
And Function ◽  
The Brain ◽  
Deficient Mice

Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

Natural Products for the Treatment of Neurodegenerative Diseases

2020 ◽  
Vol 27 (34) ◽  
pp. 5790-5828 ◽  
Author(s):  
Ze Wang ◽  
Chunyang He ◽  
Jing-Shan Shi
Keyword(s):  
Nervous System ◽  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Neuroprotective Effect ◽  
Rapid Development ◽  
New Drugs ◽  
Progressive Degeneration ◽  
Cord Injury ◽  
The Central Nervous System ◽  
And Function

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Alzheimer's Disease (AD), Parkinson's Disease (PD) and Spinal Cord Injury (SCI) are the common neurodegenerative diseases, which typically occur in people over the age of 60. With the rapid development of an aged society, over 60 million people worldwide are suffering from these uncurable diseases. Therefore, the search for new drugs and therapeutic methods has become an increasingly important research topic. Natural products especially those from the Traditional Chinese Medicines (TCMs), are the most important sources of drugs, and have received extensive interest among pharmacist. In this review, in order to facilitate further chemical modification of those useful natural products by pharmacists, we will bring together recent studies in single natural compound from TCMs with neuroprotective effect.

scholarly journals Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice

2020 ◽  
Vol 11 (1) ◽  
pp. 241-250
Author(s):  
Zhenyu Li ◽  
Guangqian Ding ◽  
Yudi Wang ◽  
Zelong Zheng ◽  
Jianping Lv
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Inflammatory Responses ◽  
Tissue Samples ◽  
Protein Levels ◽  
Virus Serotype ◽  
Transcription Factor Eb ◽  
The Brain

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

scholarly journals Regulatory Roles of Bone in Neurodegenerative Diseases

2020 ◽  
Vol 12 ◽  
Author(s):  
Zhengran Yu ◽  
Zemin Ling ◽  
Lin Lu ◽  
Jin Zhao ◽  
Xiang Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
The Elderly ◽  
Lymphoid Organ ◽  
The Body ◽  
Hematopoietic Stem ◽  
Brain Functions ◽  
And Function ◽  
The Impact ◽  
The Brain

Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.

scholarly journals SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021 ◽  
Vol 11 ◽  
Author(s):  
Ramu Manjula ◽  
Kumari Anuja ◽  
Francisco J. Alcain
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Histone Deacetylases ◽  
Neurological Diseases ◽  
Clinical Manifestations ◽  
Life Extension ◽  
Protein Homeostasis ◽  
Brain Functions ◽  
Age Related ◽  
And Function

Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.

scholarly journals Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 272
Author(s):  
Anaïs Bécot ◽  
Charlotte Volgers ◽  
Guillaume van Niel
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurodegenerative Diseases ◽  
Multivesicular Body ◽  
Precursor Protein ◽  
Aβ Peptides ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Novel Concept ◽  
The Brain

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

scholarly journals PET and the multitracer concept in the study of neurodegenerative diseases

2015 ◽  
Vol 9 (4) ◽  
pp. 343-349 ◽  
Author(s):  
Henry Engler ◽  
Andres Damian ◽  
Cecilia Bentancourt
Keyword(s):  
Positron Emission Tomography ◽  
Molecular Imaging ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Neurodegenerative Disorders ◽  
Clinical Symptoms ◽  
Emission Tomography ◽  
Positron Emission ◽  
The Brain

ABSTRACT The complexity of the pathological reactions of the brain to an aggression caused by an internal or external noxa represents a challenge for molecular imaging. Positron emission tomography (PET) can indicate in vivo,anatomopathological changes involved in the development of different clinical symptoms in patients with neurodegenerative disorders. PET and the multitracer concept can provide information from different systems in the brain tissue building an image of the whole disease. We present here the combination of 18F-flourodeoxyglucose (FDG) and N-[11C-methyl]-L-deuterodeprenyl (DED), FDG and N-[11C-methyl] 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), PIB and L-[11C]-3'4-Dihydrophenylalanine (DOPA) and finally PIB and [15O]H2O.

scholarly journals Factors of Cell Degeneration or Death caused by Mutant Tau Protein

2021 ◽  
Vol 271 ◽  
pp. 03037
Author(s):  
O Mikiko
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Protein Expression Level ◽  
Cell Degeneration ◽  
Pathological Conditions ◽  
Type Gene ◽  
And Function ◽  
Protein Dysfunction ◽  
The Brain

Tau protein is a microtubule associated protein mainly expressed in neurons. Under pathological conditions, Tau protein is abnormally hyperphosphorylated and separated from microtubules. Abnormal Tau aggregates form nerve fiber tangles, which are insoluble aggregates in the brain. It is due to the microtubule rupture caused by Tau protein dysfunction and it is associated with neurofibrillar degeneration in Alzheimer's disease.This paper studies several reports and research on the structure and function of Tau protein, the role of Tau protein in pathological diseases and its relationship with neurodegenerative diseases. This paper concludes that Tau protein has undergone abnormal modification and aggregation in many neurodegenerative diseases, but the specific type of Tau protein that causes neurotoxicity, as well as the pathogenesis of its phosphorylation and functional injury inducing nerve apoptosis, are still not fully understood. Various abnormal modifications of Tau protein occur under pathological conditions, and fatal cascade events occur at different stages of neuron apoptosis. Therefore, the causes and effects of cytotoxicity mediated by Tau protein are very complicated. Different or even opposite conclusions are sometimes drawn in Tau protein-mediated neurodegeneration studies. This may be due to differences in Tau protein type, gene mutation and protein expression level.

scholarly journals Exosomes: Future Perspective in Neurodegenerative Diseases

2020 ◽  
Vol 6 (4) ◽  
pp. 251-258
Author(s):  
Leila Alidoust ◽  
◽  
Adele Jafari ◽  
Keyword(s):  
Neurodegenerative Diseases ◽  
Future Perspective ◽  
Therapeutic Tool ◽  
Irreversible Loss ◽  
Physiological Processes ◽  
Potential Applications ◽  
And Function ◽  
The Brain ◽  
Structure And Functions

Neurodegeneration is a progressive and irreversible loss of neuronal cells in specific regions of the brain. Alzheimer Diseases (AD) Parkinson Disease (PD) are the most common forms of neurodegenerative diseases in older people. Exosomes are extracellular nanovesicles that have a key role in physiological processes such as intercellular communication, cell migration, angiogenesis, and anti-tumor immunity. Mounting evidence indicates the role of exosomes in neurodegenerative disorders as possible carriers of disease particles. They have several different potential applications thanks to their unique structure and functions. The present review summarizes recent studies on exosome potentials as a biomarker and therapeutic tool in neurodegenerative diseases. It also provides an overview of the structure and function of exosomes.

scholarly journals Neutrophils Return to Bloodstream Through the Brain Blood Vessel After Crosstalk With Microglia During LPS-Induced Neuroinflammation

2020 ◽  
Vol 8 ◽  
Author(s):  
Yu Rim Kim ◽  
Young Min Kim ◽  
Jaeho Lee ◽  
Joohyun Park ◽  
Jong Eun Lee ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Neutrophil Infiltration ◽  
Two Photon ◽  
Activated State ◽  
The Central Nervous System ◽  
Time Observation ◽  
And Function ◽  
The Brain

The circulatory neutrophil and brain tissue-resident microglia are two important immune cells involved in neuroinflammation. Since neutrophils that infiltrate through the brain vascular vessel may affect the immune function of microglia in the brain, close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and immunological aftermaths that follow. This study aimed to observe how morphology and function of both neutrophils and microglia are converted in the inflamed brain. To directly investigate cellular responses of neutrophils and microglia, LysMGFP/+ and CX3CR1GFP/+ mice were used for the observation of neutrophils and microglia, respectively. In addition, low-dose lipopolysaccharide (LPS) was utilized to induce acute inflammation in the central nervous system (CNS) of mice. Real-time observation on mice brain undergoing neuroinflammation via two-photon intravital microscopy revealed various changes in neutrophils and microglia; namely, neutrophil infiltration and movement within the brain tissue increased, while microglia displayed morphological changes suggesting an activated state. Furthermore, neutrophils seemed to not only actively interact with microglial processes but also exhibit reverse transendothelial migration (rTEM) back to the bloodstream. Thus, it may be postulated that, through crosstalk with neutrophils, macrophages are primed to initiate a neuroinflammatory immune response; also, during pathogenic events in the brain, neutrophils that engage in rTEM may deliver proinflammatory signals to peripheral organs outside the brain. Taken together, these results both show that neuroinflammation results in significant alterations in neutrophils and microglia and lay the pavement for further studies on the molecular mechanisms behind such changes.

Human neuronal cells: epigenetic aspects

2013 ◽  
Vol 4 (4) ◽  
pp. 319-333 ◽  
Author(s):  
Jessica Kukucka ◽  
Tessa Wyllie ◽  
Justin Read ◽  
Lauren Mahoney ◽  
Cenk Suphioglu
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Neuronal Cells ◽  
Hdac Inhibitors ◽  
Histone Acetyltransferases ◽  
Human Neuronal Cells ◽  
The Brain

AbstractHistone acetyltransferases (HATs) and histone deacetylases (HDACs) promote histone posttranslational modifications, which lead to an epigenetic alteration in gene expression. Aberrant regulation of HATs and HDACs in neuronal cells results in pathological consequences such as neurodegeneration. Alzheimer’s disease is the most common neurodegenerative disease of the brain, which has devastating effects on patients and loved ones. The use of pan-HDAC inhibitors has shown great therapeutic promise in ameliorating neurodegenerative ailments. Recent evidence has emerged suggesting that certain deacetylases mediate neurotoxicity, whereas others provide neuroprotection. Therefore, the inhibition of certain isoforms to alleviate neurodegenerative manifestations has now become the focus of studies. In this review, we aimed to discuss and summarize some of the most recent and promising findings of HAT and HDAC functions in neurodegenerative diseases.

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