This document summarizes the role of the transcription factor nuclear factor-kappa B (NF-κB) in the major genetic and environmental risk factors for Alzheimer's disease (AD). It discusses how NF-κB interacts with genes implicated in AD risk, such as APP, APOE, and genes involved in immunity. It reviews evidence from neuronal cell lines, invertebrate models like fruit flies, and vertebrate models like mice that genetic and environmental factors associated with aging increase NF-κB activity and are linked to AD pathology. The document suggests NF-κB may be a key regulator integrating genetic and environmental risk factors and could potentially be targeted for disease prevention.
This document summarizes research on the roles of pathogenic and physiological autoantibodies against central nervous system antigens. Pathogenic autoantibodies are studied in the context of autoimmune disorders and can lead to neurological deficits through inflammatory processes like encephalitis. However, physiological autoantibodies also exist naturally and may help maintain homeostasis. The research project explored the roles of both types of autoantibodies in central nervous system disorders, drawing conclusions from existing data and highlighting unanswered questions to propose future research directions.
Tuberculosis is a lung disease caused by the bacterium Mycobacterium tuberculosis. It remains a major global health problem. In 2020, there were an estimated 10 million new TB cases and 1.5 million TB deaths worldwide, making it one of the top 10 causes of death globally. The disease disproportionately affects low and middle income countries. Key risk factors include poverty, HIV infection and indoor air pollution. Early diagnosis and complete treatment are important for controlling the spread of the disease.
The pathogenesis of NF1 is complex and involves interrelationships between various elements that manifest at different ages. Café-au-lait spots typically appear in the first year of life, while NF2 vestibular schwannomas usually develop later in the third decade. Symptoms of Schwannomatosis also appear later in life and are non-specific, like pain. Understanding how clinical signs relate to a person's age can help with healthcare and provide insights into pathogenesis. In some cases, genetic analysis may help with diagnosis when clinical symptoms are unclear. Somatic mosaicism can also contribute to limited signs and symptoms.
Guillain Barre Syndrome (GBS) is an acute immune-mediated inflammatory neuropathy. It is the most common cause of acute flaccid paralysis worldwide. Recent decades have seen progress in understanding the epidemiology, pathogenesis, and prognosis of GBS. The pathogenesis involves molecular mimicry between gangliosides and antigens from preceding infections like Campylobacter jejuni, leading to anti-ganglioside antibody production and complement-mediated nerve damage. Different GBS subtypes are associated with different antiganglioside antibodies and clinical courses.
Apoptosis, or programmed cell death, plays an important role in development, immunity, and maintenance of genomic integrity. Disruption of apoptosis can lead to diseases like cancer, autoimmune disorders, and neurodegenerative diseases. The document discusses the key stages and molecular mechanisms of apoptosis, including the roles of caspases, Bcl-2 family proteins, and death receptors. It also covers the importance of apoptosis in processes like immune system development, tissue remodeling, and response to DNA damage. Therapeutic strategies aim to either inhibit inappropriate apoptosis or induce apoptosis in conditions like cancer.
A New Perspective On Alzheimer S Disease As A Brain Expression Of A Complex M...Tony Lisko
This document discusses Alzheimer's disease as a brain expression of a complex metabolic disorder. It summarizes that AD is characterized by abnormalities at systemic, histological, macromolecular and biochemical levels beyond amyloid plaques and neurofibrillary tangles. It proposes that cerebral hypoperfusion and metabolic stress from factors like atherosclerosis, infections and insulin resistance can trigger AD pathology by inducing oxidative damage and impairing brain energy metabolism. Specifically, it suggests that arginine and branched chain amino acid metabolism disturbances contribute to AD pathogenesis and that maintaining adequate levels of these nutrients may have therapeutic potential.
This document summarizes a study on developing a novel protein interaction platform to study neurodegeneration. The study cultured neuronal stem cells to form neurospheres, which were used as a model system. Lentiviral transfection was optimized to introduce target genes stably into the neurospheres. The goal was to analyze protein interactions of Alzheimer's disease proteins by co-immunoprecipitation of neurosphere cultures expressing tagged target proteins. This model aims to further the understanding of molecular mechanisms in neurodegenerative disorders like Alzheimer's disease.
That’s important because right now, doctors have to rely on a set of 11 criteria, which can overlap with many other diseases, to try to make a diagnosis.
“It is one of the most complex clinical diagnoses,” says Pascual, who is also a practicing pediatric rheumatologist.
“It might lead to better diagnostic tests, but we don’t know that yet,” Pascual says. Other experts say the discoveries will most certainly lead to new drug targets.
Systemic lupus erythematosus (also called SLE or lupus)
is an autoimmune condition. The normal role of your
body’s immune system is to fight off infections and
diseases to keep you healthy. In an autoimmune disease
like lupus, your immune system starts attacking your
own healthy tissues. For some people lupus may just
affect the skin and/or joints. In other people the lungs,
kidneys, blood vessels,
This document summarizes research on the roles of pathogenic and physiological autoantibodies against central nervous system antigens. Pathogenic autoantibodies are studied in the context of autoimmune disorders and can lead to neurological deficits through inflammatory processes like encephalitis. However, physiological autoantibodies also exist naturally and may help maintain homeostasis. The research project explored the roles of both types of autoantibodies in central nervous system disorders, drawing conclusions from existing data and highlighting unanswered questions to propose future research directions.
Tuberculosis is a lung disease caused by the bacterium Mycobacterium tuberculosis. It remains a major global health problem. In 2020, there were an estimated 10 million new TB cases and 1.5 million TB deaths worldwide, making it one of the top 10 causes of death globally. The disease disproportionately affects low and middle income countries. Key risk factors include poverty, HIV infection and indoor air pollution. Early diagnosis and complete treatment are important for controlling the spread of the disease.
The pathogenesis of NF1 is complex and involves interrelationships between various elements that manifest at different ages. Café-au-lait spots typically appear in the first year of life, while NF2 vestibular schwannomas usually develop later in the third decade. Symptoms of Schwannomatosis also appear later in life and are non-specific, like pain. Understanding how clinical signs relate to a person's age can help with healthcare and provide insights into pathogenesis. In some cases, genetic analysis may help with diagnosis when clinical symptoms are unclear. Somatic mosaicism can also contribute to limited signs and symptoms.
Guillain Barre Syndrome (GBS) is an acute immune-mediated inflammatory neuropathy. It is the most common cause of acute flaccid paralysis worldwide. Recent decades have seen progress in understanding the epidemiology, pathogenesis, and prognosis of GBS. The pathogenesis involves molecular mimicry between gangliosides and antigens from preceding infections like Campylobacter jejuni, leading to anti-ganglioside antibody production and complement-mediated nerve damage. Different GBS subtypes are associated with different antiganglioside antibodies and clinical courses.
Apoptosis, or programmed cell death, plays an important role in development, immunity, and maintenance of genomic integrity. Disruption of apoptosis can lead to diseases like cancer, autoimmune disorders, and neurodegenerative diseases. The document discusses the key stages and molecular mechanisms of apoptosis, including the roles of caspases, Bcl-2 family proteins, and death receptors. It also covers the importance of apoptosis in processes like immune system development, tissue remodeling, and response to DNA damage. Therapeutic strategies aim to either inhibit inappropriate apoptosis or induce apoptosis in conditions like cancer.
A New Perspective On Alzheimer S Disease As A Brain Expression Of A Complex M...Tony Lisko
This document discusses Alzheimer's disease as a brain expression of a complex metabolic disorder. It summarizes that AD is characterized by abnormalities at systemic, histological, macromolecular and biochemical levels beyond amyloid plaques and neurofibrillary tangles. It proposes that cerebral hypoperfusion and metabolic stress from factors like atherosclerosis, infections and insulin resistance can trigger AD pathology by inducing oxidative damage and impairing brain energy metabolism. Specifically, it suggests that arginine and branched chain amino acid metabolism disturbances contribute to AD pathogenesis and that maintaining adequate levels of these nutrients may have therapeutic potential.
This document summarizes a study on developing a novel protein interaction platform to study neurodegeneration. The study cultured neuronal stem cells to form neurospheres, which were used as a model system. Lentiviral transfection was optimized to introduce target genes stably into the neurospheres. The goal was to analyze protein interactions of Alzheimer's disease proteins by co-immunoprecipitation of neurosphere cultures expressing tagged target proteins. This model aims to further the understanding of molecular mechanisms in neurodegenerative disorders like Alzheimer's disease.
That’s important because right now, doctors have to rely on a set of 11 criteria, which can overlap with many other diseases, to try to make a diagnosis.
“It is one of the most complex clinical diagnoses,” says Pascual, who is also a practicing pediatric rheumatologist.
“It might lead to better diagnostic tests, but we don’t know that yet,” Pascual says. Other experts say the discoveries will most certainly lead to new drug targets.
Systemic lupus erythematosus (also called SLE or lupus)
is an autoimmune condition. The normal role of your
body’s immune system is to fight off infections and
diseases to keep you healthy. In an autoimmune disease
like lupus, your immune system starts attacking your
own healthy tissues. For some people lupus may just
affect the skin and/or joints. In other people the lungs,
kidneys, blood vessels,
Austin Journal of Multiple Sclerosis & Neuroimmunology is an open access, peer review Journal publishing original research & review articles on aetiology, epidemiology, and pathogenesis of inflammatory demyelinating diseases of the central nervous system. Austin Journal of Multiple Sclerosis & Neuroimmunology is aimed to provide a strong platform for challenging cases that includes but not excludes the damage of insulating covers of both central nervous system and spine. It is a grounding platform for all neurologists, neuroimmunologists, neurovirologists, researchers, medical doctors, health professionals, scientists, and scholars to publish their research work & update the latest research information.
Topics include but not limited to Clinical Neurology, Biomarkers, Glial, Myelin Chemistry, Neuroimaging, Neuropathology, Neuroepidemiology, Therapeutics, Genetics/Transcriptomics, Experimental Models, Pathobiology, Neuroimmunology, Neuropsychology, Neurorehabilitation, Pathobiology of the Brain, Psychology, Measurement Scales, Teaching, and Neuroethics.
Austin Journal of Multiple Sclerosis & Neuroimmunology supports the scientific transformation and fortification in Medical and Clinical research community by magnifying access to peer reviewed scientific literary works. Austin also brings universally peer reviewed member journals under one roof thereby promoting knowledge sharing, collaborative and promotion of multidisciplinary science.
This study investigated whether Alpinae Oxyphyllae Fructus (AE), a traditional Chinese medicine, could improve M1 and M2 microglial polarization, inhibit neuroinflammation through the triggering receptor expressed on myeloid cells 2 (TREM2), and exert anti-inflammatory effects. Methods used included cytokine assays, immunofluorescence staining, western blot, and RT-PCR to analyze proteins and genes involved in the TREM2 pathway and neuroinflammation. The findings indicated that AE could improve the polarization response of microglia. TREM2 plays a vital role in the microglial repolarization effects of AE through regulating neuroinflammation signaling pathways.
Tryptophan metabolism and the kynurenine pathway play an important role in neuropsychiatric disorders and immune regulation. Tryptophan is converted to kynurenine via the enzymes IDO and TDO, with kynurenine then processed differently by astrocytes and microglia in the brain. Pro-inflammatory cytokines increase IDO/TDO activity, depleting tryptophan and producing neurotoxic metabolites, while anti-inflammatory cytokines decrease their activity. Abnormalities in this pathway have been linked to depression, psychosis, Alzheimer's, and autoimmune diseases. IDO also plays a key role in immune tolerance by inhibiting T-cell responses and preventing rejection of the fetus during
Ms preventable & strategies for remissionmorwenna2
This document discusses the causes and treatment of multiple sclerosis from a holistic perspective. It argues that MS and other chronic autoimmune diseases are caused by a combination of dietary deficiencies, viruses, and bacteria interacting in the gut. It summarizes research showing how gut bacteria can trigger autoimmune responses. The document advocates treating and preventing MS through diet, exercise, plant medicine, and focusing on gut health in order to strengthen immunity. Sugar and processed foods are identified as inflammatory and as providing an environment for harmful bacteria and viruses to thrive.
This review article discusses Alzheimer's disease pathogenesis and the role of autophagy and mitophagy, with a focus on microglia. It first provides background on AD as the most common form of dementia. The key hallmarks of AD are amyloid plaques and neurofibrillary tangles composed of tau protein. Impaired autophagy and mitophagy are also involved in AD pathogenesis. Microglia are immune cells in the brain that normally support neurons but in AD contribute to neuroinflammation. The review discusses evidence that autophagy and mitophagy are impaired in microglia in AD, and that neuroinflammation and impaired degradation pathways interact and form vicious cycles that drive AD
This document summarizes research on amyotrophic lateral sclerosis (ALS), including its pathogenesis, genetic factors, and potential new treatment strategies. It discusses how ALS results from damage to motor neurons in the brain and spinal cord from a combination of increased toxicity from substances like glutamate, calcium ions, and protein aggregates as well as weaknesses in the motor neuron system from genetic mutations and deficits in neurotrophic factors. While the cause is still unclear, various studies suggest roles for inflammation, immune responses, oxidative stress, cytoskeletal abnormalities, and dysregulation of autophagy and microRNAs. The document reviews several studies examining these pathways and their implications for understanding ALS and identifying new therapeutic targets. It also proposes experimental models to
This document summarizes research on the immunological and toxicological implications of COVID-19, focusing on the innate immune response and immune evasion. It discusses how the virus can trigger a "cytokine storm" through overactivation of the innate immune system and proinflammatory cytokines like IL-6. This storm can lead to widespread inflammation and multi-organ failure. The document also explores potential therapeutic strategies aimed at modulating the cytokine response, such as using corticosteroids or chloroquine to reduce IL-6 levels and calm the storm. Understanding the immune dysregulation and identifying key signaling pathways may help develop new clinical management approaches and prevent progression to severe illness.
This document summarizes a book titled "Role of Plants, environmental toxins and physical neurotoxicological factors in Amyotrophic lateral sclerosis, Alzheimer Disease and Other Neurodegenerative Diseases." It has 10 authors from various countries. The book aims to observe the effects of plant neurotoxins, physical factors, and geography on neurodegenerative diseases like ALS, PD, and AD. It reviews literature on geographic clusters of these diseases and genetic mutations. It also discusses the brain's high metabolic needs, interactions between neurons and astrocytes, and how impairments in these systems can lead to neurodegeneration. The book presents figures and intends to develop new hypotheses and therapies based on contributing pathogenic factors.
shift in brain metabolism in late onset ad- implications for biomarkers and t...Lauren Klosinski
This document discusses a shift in brain metabolism in late onset Alzheimer's disease and implications for biomarkers and therapeutic interventions. It proposes that mitochondrial bioenergetic deficits and brain hypometabolism occur early in Alzheimer's pathogenesis and lead to increased amyloid beta production and oxidative stress. This results in a shift from glucose-driven bioenergetics to a less efficient ketogenic/fatty acid pathway, eventually causing white matter degeneration. Targeting brain metabolism through interventions that enhance glucose metabolism or activate ketogenic pathways may help prevent or delay disease progression.
Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the joints. Genetic and environmental factors contribute to its pathogenesis. Genome-wide analyses have identified genes related to immune regulation that increase the risk of developing rheumatoid arthritis. Environmental triggers such as smoking can interact with genetic susceptibility factors like HLA-DRB1 alleles to further increase the risk. This leads to a breakdown of self-tolerance and production of autoantibodies against citrullinated proteins. While the cause is unknown, it is believed that citrullination of proteins by enzymes like peptidyl arginine deiminase 4 results in the formation of neo-epitopes that elicit an autoimmune response. This prearthritis phase
This document examines the encephalogenic and HLA-DR binding capacities of various myelin peptides. It constructs recombinant HLA-DRβ1 complexes containing peptides from myelin proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin basic protein. These complexes are transfected into insect cells to evaluate surface expression and autoantigenic activity. Individual myelin peptides are also tested for their ability to induce experimental autoimmune encephalomyelitis in transgenic mice. The data shows that two specific sheath peptides induced multiple sclerosis-like paralysis when injected into HLA-DRβ1-15.01 mice, indicating a role in multiple sclerosis induction. Ultimately, the peptide-HLA complexes will be used
Prevalence of Gene Polymorphisms in Intervertebral Disc Degenerative Diseasesijtsrd
Intervertebral disc diseases is otherwise known as breakdown of one or more discs that separate the bone of the spine, Which cause pain in the back, neck as well as frequent pain in legs and arms. The general role of intervertebral discs is to provide the cushioning between vertebrae and absorb the pressure that is exerted on the spine. Generally low back pain LBP is considered as common disorder from disc degenerative diseases. The main reason of the LBP is due to contribution of intervertebral disc diseases and combination of genetic and environmental factors. Most of these factor identified , But some of these remain unidentified. However recent researches identified that variations in several genes may influence the risc of intervertebral disc diseases . Most of the variations associated with genes related with immune function leads to increase risk of intervertebral disc diseases . Most of these genes plays a vital role in immune response like inflammation and water loss dehydration of the discs, Which causes their degeneration. This review focuses on the evidence of genetic disposition, the genes or biological processes that are implicated, and the need to consolidate resources and clarify phenotype definition to take advantage of the new technologies in genetic analysis to enhance our understanding of this condition. Mr. C. Marimuthu | Dr. V. Pushpa Rani | Dr. V. Judia Harriet Sumathy "Prevalence of Gene Polymorphisms in Intervertebral Disc Degenerative Diseases" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-2 , February 2019, URL: https://www.ijtsrd.com/papers/ijtsrd19153.pdf
Paper URL: https://www.ijtsrd.com/biological-science/molecular-biology/19153/prevalence-of-gene-polymorphisms-in-intervertebral-disc-degenerative-diseases/mr-c-marimuthu
This document discusses several gene polymorphisms that may be associated with variations in atherosclerosis within and between populations. It summarizes studies looking at polymorphisms in genes involved in lipid metabolism, inflammation/immune response, and endothelial function that influence atherosclerosis risk and outcomes. While genes like K-ras are strongly associated with certain cancers, the document questions whether a similarly strong gene or group of genes will be discovered for atherosclerosis, given it is a complex disease with many genetic and environmental factors.
1) ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle paralysis. It was first described in 1874 but its pathogenesis remains unclear.
2) ALS may be caused by both increased toxicity from substances like RNA proteins and weakness of the motor neuron system. Genetic mutations and environmental toxins are also implicated in some cases.
3) The document proposes new experimental and drug delivery approaches to better understand disease mechanisms and improve treatment of ALS.
The document discusses the relationship between the immune system and brain conditions from a toxicological perspective. It summarizes several studies that found:
1) The immune system plays an important role in brain development and any immune activation during development can affect later neural function, immune function, mood and cognition.
2) A drug called fingolimod that modulates sphingosine-1-phosphate receptors, reducing lymphocyte migration from lymph nodes, significantly reduced relapse rates and disability progression in multiple sclerosis patients compared to placebo.
3) Systemic immune status can influence local brain tissue conditions, and this effect could be considered a type of toxicological effect worth further investigation to better understand disease pathogenesis and develop new pharmacological
Genetic Insights Into Multiple Sclerosis PathogenesisAaron Sparshott
A segment of a group presentation reflecting upon some of the genetic components that may contribute to Multiple Sclerosis pathogenesis.
IL2Rα and IL7Rα were the two genes of focus.
(This presentation was originally done for Semester 2 , 2008)
CAR-T cells are genetically modified T cells that are designed to target and destroy cancer cells. They contain chimeric antigen receptors (CARs) that allow them to recognize specific antigens on tumor cells independently of the normal T cell receptor. The CAR is composed of an extracellular antigen recognition domain attached to transmembrane and co-stimulatory domains, allowing the modified T cells to directly bind and kill cancer cells upon antigen recognition and initiate an immune response against the tumor.
This webinar discusses immunometabolism and its relationship to COVID-19. It explores how elevated glucose levels can favor SARS-CoV-2 infection by inducing viral replication and cytokine expression through a HIF-1α/glycolysis pathway. Insulin treatment is also discussed and its association with increased mortality in COVID-19 patients with diabetes. The role of mitochondria in producing reactive oxygen species during infection is covered, as is the potential for antioxidants and dietary changes like ketogenic diets to impact the immune response. Biomarkers of immunometabolism are proposed for monitoring clinical outcomes.
Neurobiology of Alzheimer’s disease
Role of Acetyl choline
Amyloid-beta-mediated neurodegeneration
Amyloid beta accumulation
Amyloid cascade hypothesis
Microtubule-associated protein tau
Oxidative stress
ROS-mediated neuronal damage
This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
How to Make a Field Mandatory in Odoo 17Celine George
In Odoo, making a field required can be done through both Python code and XML views. When you set the required attribute to True in Python code, it makes the field required across all views where it's used. Conversely, when you set the required attribute in XML views, it makes the field required only in the context of that particular view.
Austin Journal of Multiple Sclerosis & Neuroimmunology is an open access, peer review Journal publishing original research & review articles on aetiology, epidemiology, and pathogenesis of inflammatory demyelinating diseases of the central nervous system. Austin Journal of Multiple Sclerosis & Neuroimmunology is aimed to provide a strong platform for challenging cases that includes but not excludes the damage of insulating covers of both central nervous system and spine. It is a grounding platform for all neurologists, neuroimmunologists, neurovirologists, researchers, medical doctors, health professionals, scientists, and scholars to publish their research work & update the latest research information.
Topics include but not limited to Clinical Neurology, Biomarkers, Glial, Myelin Chemistry, Neuroimaging, Neuropathology, Neuroepidemiology, Therapeutics, Genetics/Transcriptomics, Experimental Models, Pathobiology, Neuroimmunology, Neuropsychology, Neurorehabilitation, Pathobiology of the Brain, Psychology, Measurement Scales, Teaching, and Neuroethics.
Austin Journal of Multiple Sclerosis & Neuroimmunology supports the scientific transformation and fortification in Medical and Clinical research community by magnifying access to peer reviewed scientific literary works. Austin also brings universally peer reviewed member journals under one roof thereby promoting knowledge sharing, collaborative and promotion of multidisciplinary science.
This study investigated whether Alpinae Oxyphyllae Fructus (AE), a traditional Chinese medicine, could improve M1 and M2 microglial polarization, inhibit neuroinflammation through the triggering receptor expressed on myeloid cells 2 (TREM2), and exert anti-inflammatory effects. Methods used included cytokine assays, immunofluorescence staining, western blot, and RT-PCR to analyze proteins and genes involved in the TREM2 pathway and neuroinflammation. The findings indicated that AE could improve the polarization response of microglia. TREM2 plays a vital role in the microglial repolarization effects of AE through regulating neuroinflammation signaling pathways.
Tryptophan metabolism and the kynurenine pathway play an important role in neuropsychiatric disorders and immune regulation. Tryptophan is converted to kynurenine via the enzymes IDO and TDO, with kynurenine then processed differently by astrocytes and microglia in the brain. Pro-inflammatory cytokines increase IDO/TDO activity, depleting tryptophan and producing neurotoxic metabolites, while anti-inflammatory cytokines decrease their activity. Abnormalities in this pathway have been linked to depression, psychosis, Alzheimer's, and autoimmune diseases. IDO also plays a key role in immune tolerance by inhibiting T-cell responses and preventing rejection of the fetus during
Ms preventable & strategies for remissionmorwenna2
This document discusses the causes and treatment of multiple sclerosis from a holistic perspective. It argues that MS and other chronic autoimmune diseases are caused by a combination of dietary deficiencies, viruses, and bacteria interacting in the gut. It summarizes research showing how gut bacteria can trigger autoimmune responses. The document advocates treating and preventing MS through diet, exercise, plant medicine, and focusing on gut health in order to strengthen immunity. Sugar and processed foods are identified as inflammatory and as providing an environment for harmful bacteria and viruses to thrive.
This review article discusses Alzheimer's disease pathogenesis and the role of autophagy and mitophagy, with a focus on microglia. It first provides background on AD as the most common form of dementia. The key hallmarks of AD are amyloid plaques and neurofibrillary tangles composed of tau protein. Impaired autophagy and mitophagy are also involved in AD pathogenesis. Microglia are immune cells in the brain that normally support neurons but in AD contribute to neuroinflammation. The review discusses evidence that autophagy and mitophagy are impaired in microglia in AD, and that neuroinflammation and impaired degradation pathways interact and form vicious cycles that drive AD
This document summarizes research on amyotrophic lateral sclerosis (ALS), including its pathogenesis, genetic factors, and potential new treatment strategies. It discusses how ALS results from damage to motor neurons in the brain and spinal cord from a combination of increased toxicity from substances like glutamate, calcium ions, and protein aggregates as well as weaknesses in the motor neuron system from genetic mutations and deficits in neurotrophic factors. While the cause is still unclear, various studies suggest roles for inflammation, immune responses, oxidative stress, cytoskeletal abnormalities, and dysregulation of autophagy and microRNAs. The document reviews several studies examining these pathways and their implications for understanding ALS and identifying new therapeutic targets. It also proposes experimental models to
This document summarizes research on the immunological and toxicological implications of COVID-19, focusing on the innate immune response and immune evasion. It discusses how the virus can trigger a "cytokine storm" through overactivation of the innate immune system and proinflammatory cytokines like IL-6. This storm can lead to widespread inflammation and multi-organ failure. The document also explores potential therapeutic strategies aimed at modulating the cytokine response, such as using corticosteroids or chloroquine to reduce IL-6 levels and calm the storm. Understanding the immune dysregulation and identifying key signaling pathways may help develop new clinical management approaches and prevent progression to severe illness.
This document summarizes a book titled "Role of Plants, environmental toxins and physical neurotoxicological factors in Amyotrophic lateral sclerosis, Alzheimer Disease and Other Neurodegenerative Diseases." It has 10 authors from various countries. The book aims to observe the effects of plant neurotoxins, physical factors, and geography on neurodegenerative diseases like ALS, PD, and AD. It reviews literature on geographic clusters of these diseases and genetic mutations. It also discusses the brain's high metabolic needs, interactions between neurons and astrocytes, and how impairments in these systems can lead to neurodegeneration. The book presents figures and intends to develop new hypotheses and therapies based on contributing pathogenic factors.
shift in brain metabolism in late onset ad- implications for biomarkers and t...Lauren Klosinski
This document discusses a shift in brain metabolism in late onset Alzheimer's disease and implications for biomarkers and therapeutic interventions. It proposes that mitochondrial bioenergetic deficits and brain hypometabolism occur early in Alzheimer's pathogenesis and lead to increased amyloid beta production and oxidative stress. This results in a shift from glucose-driven bioenergetics to a less efficient ketogenic/fatty acid pathway, eventually causing white matter degeneration. Targeting brain metabolism through interventions that enhance glucose metabolism or activate ketogenic pathways may help prevent or delay disease progression.
Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the joints. Genetic and environmental factors contribute to its pathogenesis. Genome-wide analyses have identified genes related to immune regulation that increase the risk of developing rheumatoid arthritis. Environmental triggers such as smoking can interact with genetic susceptibility factors like HLA-DRB1 alleles to further increase the risk. This leads to a breakdown of self-tolerance and production of autoantibodies against citrullinated proteins. While the cause is unknown, it is believed that citrullination of proteins by enzymes like peptidyl arginine deiminase 4 results in the formation of neo-epitopes that elicit an autoimmune response. This prearthritis phase
This document examines the encephalogenic and HLA-DR binding capacities of various myelin peptides. It constructs recombinant HLA-DRβ1 complexes containing peptides from myelin proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin basic protein. These complexes are transfected into insect cells to evaluate surface expression and autoantigenic activity. Individual myelin peptides are also tested for their ability to induce experimental autoimmune encephalomyelitis in transgenic mice. The data shows that two specific sheath peptides induced multiple sclerosis-like paralysis when injected into HLA-DRβ1-15.01 mice, indicating a role in multiple sclerosis induction. Ultimately, the peptide-HLA complexes will be used
Prevalence of Gene Polymorphisms in Intervertebral Disc Degenerative Diseasesijtsrd
Intervertebral disc diseases is otherwise known as breakdown of one or more discs that separate the bone of the spine, Which cause pain in the back, neck as well as frequent pain in legs and arms. The general role of intervertebral discs is to provide the cushioning between vertebrae and absorb the pressure that is exerted on the spine. Generally low back pain LBP is considered as common disorder from disc degenerative diseases. The main reason of the LBP is due to contribution of intervertebral disc diseases and combination of genetic and environmental factors. Most of these factor identified , But some of these remain unidentified. However recent researches identified that variations in several genes may influence the risc of intervertebral disc diseases . Most of the variations associated with genes related with immune function leads to increase risk of intervertebral disc diseases . Most of these genes plays a vital role in immune response like inflammation and water loss dehydration of the discs, Which causes their degeneration. This review focuses on the evidence of genetic disposition, the genes or biological processes that are implicated, and the need to consolidate resources and clarify phenotype definition to take advantage of the new technologies in genetic analysis to enhance our understanding of this condition. Mr. C. Marimuthu | Dr. V. Pushpa Rani | Dr. V. Judia Harriet Sumathy "Prevalence of Gene Polymorphisms in Intervertebral Disc Degenerative Diseases" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-2 , February 2019, URL: https://www.ijtsrd.com/papers/ijtsrd19153.pdf
Paper URL: https://www.ijtsrd.com/biological-science/molecular-biology/19153/prevalence-of-gene-polymorphisms-in-intervertebral-disc-degenerative-diseases/mr-c-marimuthu
This document discusses several gene polymorphisms that may be associated with variations in atherosclerosis within and between populations. It summarizes studies looking at polymorphisms in genes involved in lipid metabolism, inflammation/immune response, and endothelial function that influence atherosclerosis risk and outcomes. While genes like K-ras are strongly associated with certain cancers, the document questions whether a similarly strong gene or group of genes will be discovered for atherosclerosis, given it is a complex disease with many genetic and environmental factors.
1) ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle paralysis. It was first described in 1874 but its pathogenesis remains unclear.
2) ALS may be caused by both increased toxicity from substances like RNA proteins and weakness of the motor neuron system. Genetic mutations and environmental toxins are also implicated in some cases.
3) The document proposes new experimental and drug delivery approaches to better understand disease mechanisms and improve treatment of ALS.
The document discusses the relationship between the immune system and brain conditions from a toxicological perspective. It summarizes several studies that found:
1) The immune system plays an important role in brain development and any immune activation during development can affect later neural function, immune function, mood and cognition.
2) A drug called fingolimod that modulates sphingosine-1-phosphate receptors, reducing lymphocyte migration from lymph nodes, significantly reduced relapse rates and disability progression in multiple sclerosis patients compared to placebo.
3) Systemic immune status can influence local brain tissue conditions, and this effect could be considered a type of toxicological effect worth further investigation to better understand disease pathogenesis and develop new pharmacological
Genetic Insights Into Multiple Sclerosis PathogenesisAaron Sparshott
A segment of a group presentation reflecting upon some of the genetic components that may contribute to Multiple Sclerosis pathogenesis.
IL2Rα and IL7Rα were the two genes of focus.
(This presentation was originally done for Semester 2 , 2008)
CAR-T cells are genetically modified T cells that are designed to target and destroy cancer cells. They contain chimeric antigen receptors (CARs) that allow them to recognize specific antigens on tumor cells independently of the normal T cell receptor. The CAR is composed of an extracellular antigen recognition domain attached to transmembrane and co-stimulatory domains, allowing the modified T cells to directly bind and kill cancer cells upon antigen recognition and initiate an immune response against the tumor.
This webinar discusses immunometabolism and its relationship to COVID-19. It explores how elevated glucose levels can favor SARS-CoV-2 infection by inducing viral replication and cytokine expression through a HIF-1α/glycolysis pathway. Insulin treatment is also discussed and its association with increased mortality in COVID-19 patients with diabetes. The role of mitochondria in producing reactive oxygen species during infection is covered, as is the potential for antioxidants and dietary changes like ketogenic diets to impact the immune response. Biomarkers of immunometabolism are proposed for monitoring clinical outcomes.
Neurobiology of Alzheimer’s disease
Role of Acetyl choline
Amyloid-beta-mediated neurodegeneration
Amyloid beta accumulation
Amyloid cascade hypothesis
Microtubule-associated protein tau
Oxidative stress
ROS-mediated neuronal damage
This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
How to Make a Field Mandatory in Odoo 17Celine George
In Odoo, making a field required can be done through both Python code and XML views. When you set the required attribute to True in Python code, it makes the field required across all views where it's used. Conversely, when you set the required attribute in XML views, it makes the field required only in the context of that particular view.
How to Setup Warehouse & Location in Odoo 17 InventoryCeline George
In this slide, we'll explore how to set up warehouses and locations in Odoo 17 Inventory. This will help us manage our stock effectively, track inventory levels, and streamline warehouse operations.
This presentation was provided by Steph Pollock of The American Psychological Association’s Journals Program, and Damita Snow, of The American Society of Civil Engineers (ASCE), for the initial session of NISO's 2024 Training Series "DEIA in the Scholarly Landscape." Session One: 'Setting Expectations: a DEIA Primer,' was held June 6, 2024.
This document provides an overview of wound healing, its functions, stages, mechanisms, factors affecting it, and complications.
A wound is a break in the integrity of the skin or tissues, which may be associated with disruption of the structure and function.
Healing is the body’s response to injury in an attempt to restore normal structure and functions.
Healing can occur in two ways: Regeneration and Repair
There are 4 phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This document also describes the mechanism of wound healing. Factors that affect healing include infection, uncontrolled diabetes, poor nutrition, age, anemia, the presence of foreign bodies, etc.
Complications of wound healing like infection, hyperpigmentation of scar, contractures, and keloid formation.
How to Fix the Import Error in the Odoo 17Celine George
An import error occurs when a program fails to import a module or library, disrupting its execution. In languages like Python, this issue arises when the specified module cannot be found or accessed, hindering the program's functionality. Resolving import errors is crucial for maintaining smooth software operation and uninterrupted development processes.
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1. December 2017 | Volume 8 | Article 1805
1
Mini Review
published: 11 December 2017
doi: 10.3389/fimmu.2017.01805
Frontiers in Immunology | www.frontiersin.org
Edited by:
Masaaki Murakami,
Hokkaido University, Japan
Reviewed by:
Ché Serguera,
Institut National de la Santé et de la
Recherche Médicale, France
Mireia Guerau-de-Arellano,
The Ohio State University,
United States
*Correspondence:
Ilias Kounatidis
ilias.kounatidis@bioch.ox.ac.uk
Specialty section:
This article was submitted to Multiple
Sclerosis and Neuroimmunology,
a section of the journal
Frontiers in Immunology
Received: 31 August 2017
Accepted: 30 November 2017
Published: 11 December 2017
Citation:
Jones SV and Kounatidis I (2017)
Nuclear Factor-Kappa B and
Alzheimer Disease, Unifying
Genetic and Environmental Risk
Factors from Cell to Humans.
Front. Immunol. 8:1805.
doi: 10.3389/fimmu.2017.01805
N
Simon Vann Jones1
and Ilias Kounatidis2
*
1
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom, 2
Laboratory of Cell Biology,
Development and Genetics, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Alzheimer’s disease (AD) is the most common form of dementia, an eversible, progres-
sive disease that causes problems with memory, thinking, language, planning, and
behavior. There are a number of risk factors associated with developing AD but the
exact cause remains unknown. The predominant theory is that excessive build-up of
amyloid protein leads to cell death, brain atrophy, and cognitive and functional decline.
However, the amyloid hypothesis has not led to a single successful treatment. The
recent failure of Solanezumab, a monoclonal antibody to amyloid, in a large phase III
trial was emblematic of the repeated failure of anti-amyloid therapeutics. New disease
targets are urgently needed. The innate immune system is increasingly being implicated
in the pathology of number of chronic diseases. This focused review will summarize
the role of transcription factor nuclear factor-kappa B (NF-κB), a key regulator of innate
immunity, in the major genetic and environmental risk factors in cellular, invertebrate
and vertebrate models of AD. The paper will also explore the relationship between
NF-κB and emerging environmental risk factors in an attempt to assess the potential
for this transcription factor to be targeted for disease prevention.
Keywords: nuclear factor-kappa B, Alzheimer, dementia, cell lines, invertebrate models, rodents, humans
INTRODUCTION
The global burden of dementia is devastating, with an estimated 35 million people affected and
the annual cost estimated to exceed $1 trillion by 2018 (1, 2). Despite greater knowledge of the
pathogenic sequelae of disease, repeated failure in drug trials has led to a switch in emphasis from
disease treatment to disease prevention (3–5). Alzheimer’s disease (AD) is the most common
dementia subtype yet no single theory has been able to account for the multiple risk factors leading
to the pathological and clinical features (3). The deposition of excess extracellular beta amyloid
(Aβ) protein and subsequent taupathy has long been felt to be a cause of the disease overshadowing
alternative hypotheses including microglial dysfunction, vascular disease, mitochondrial insuf-
ficiency, and metabolic disease.
However, the recent failure of another promising anti-amyloid treatment in large phase III trials
has dealt a significant blow to the credibility of the amyloid hypothesis (6). The pathognomonic
role of Aβ is now also being questioned with the discovery that Aβ acts as an antimicrobial peptide
(AMP) in cell lines, nematode, and rodent models. Aβ production following exposure to neurotoxic
fungi and bacteria provided significant neuroprotection (7). Amyloid over-production may therefore
2. Table 1 | Emerging genetic risk factors for Alzheimer’s disease (AD) and their associated with nuclear factor-kappa B (NF-κB) and amyloid (8).
Gene implicated
in late onset AD
Function Increased risk of AD Interaction with NF-κB Interaction with amyloid
TREM2 Immunity Reduced expression increases
risk: slight–medium
NF-κB suppresses hippocampal TREM2 expression (9) TREM2 required for microglial
amyloid clearance (9)
CD33 Immunity Mild CD33 activates NF-κB in myeloid cells CD33 inhibits microglial Aβ
uptake and clearance (10)
CR1 Immunity Mild–medium Microglial CR1 activation associated with increase in NF-κB (11) Uncertain (11)
INPP5D Immunity Mild Negative regulator of NF-κB expression (12) Uncertain
2
Jones and Kounatidis NF-κB and Alzheimer Disease
Frontiers in Immunology | www.frontiersin.org December 2017 | Volume 8 | Article 1805
be a downstream product of immune dysregulation rather than
a disease process in itself. In support of this, several genes are
involved in innate immunity are associated with an increase in
AD (8) (see Table 1). More work is clearly needed to explore the
interaction between amyloid and the innate immune system.
Aging is the most significant risk factor for developing AD
and recent findings have shown tissue specific brain inflam-
mation, mediated by NF-κB is associated with aging (12–15).
Hypothalamic NF-κB levels are negligible in young mice and
Drosophila. Significant activation begins in middle age. The
resulting downstream increase in AMPs leads to increased
local microglial activity, subsequent decline in gonadotrophins
and aging (12, 14). Interestingly, hypothalamic inflammation is
relatively higher when compared to neurons and glial cells in
other vulnerable brain regions such as the hippocampus (12). In
support of this hypothalamic-specific regulation of aging, drugs
known to extend lifespan in mice reduce hypothalamic inflam-
mation but have little anti-inflammatory effect on hippocampal
neurons (14).
Known inducers of NF-κB activity are highly variable and
include reactive oxygen species (ROS), interleukin 1-beta (IL-
1β), tumor necrosis factor alpha (TNF-α), bacterial lipopolysac-
charides (LPS), isoproterenol, and ionizing radiation (16, 17). In
addition to stimuli that activate NF-κB in other tissues, NF-κB
in the nervous system can be activated by growth factors and
synaptic transmission such as glutamate (18). These activators of
NF-κB in the nervous system all converge upon the inhibitor of
kinase kinase (IKK) complex (Figure 1).
Nuclear factor-kappa B transcription factors include a col-
lection of proteins with functions conserved from the fruit fly
Drosophila melanogaster to rodents and to humans (Figures 1
and 2). They are present in all human and most animal cells
and regulate the expression of more than 400 genes, including
a multitude of inflammatory mediators associated with a variety
of chronic inflammatory diseases including cancer, diabetes, and
AD (19, 20). Lately, Rel/NF-κB homologs have also been found
to occur even in organisms as simple as Cnidarians (e.g., sea
anemones and corals), Porifera (sponges), and the single-celled
eukaryote Capsaspora owczarzaki, but are notably absent in yeast
and the nematode Caenorhabditis elegans (21). Activated NF-κB
regulates the expression of specific genes, including isoforms
of SET, directly implicated in the pathogenesis of AD (22).
Conversely, expression of the mammalian family of Sirtuin dea-
cetylases, known to attenuate the effects of aging, down regulates
NF-κB (23, 24).
Studies of aging populations have enabled the identification
of a number of genetic and environmental risk factors that
appear to influence susceptibility to developing AD (25, 26). This
paper will review the interaction between these risk factors and
NF-κB, first looking at the major known genetic risk factors in
cell, invertebrate, and vertebrate models. It will then focus on the
major known environmental risk factors in these models before
reviewing emerging environmental risk factors. Finally, the paper
will review protective mechanisms across various experimental
models and whether their association with NF-κB.
The repeated failure of disease modifying trials in AD
demands that new treatment targets are urgently identified. The
recent findings that implicate the innate immune system in AD
provides an opportunity to review the evidence for NF-κB as a
key immune system regulator in the prodromal stage in the hope
of identifying a target for treatment and prevention.
GENETICS
Neuronal Cell Lines/Human Autopsy
Studies
Overexpression of the amyloid precursor protein (APP) gene is
associated with familial aggregation of late onset AD and dramati-
callyincreasessusceptibilitytoearlyADinDown’ssyndrome.APP
is cleaved by the beta-secreatase BACE1 into amyloid monomers
that form oligomers that eventually become plaques in the brain
and vasculature. Both BACE1 and NF-κB are increased in the
brains of AD patients, with NF-κB directly upregulating BACE1
and the APP gene (27, 28). Medications such as minocycline, that
inhibit NF-κB but not BACE1 or APP, reverse this process (28, 29).
The e4 variant of the APOE gene, which codes for a cholesterol
transporting protein, is the largest, single gene risk factor for AD
(30). In APOE e4-positive Schwann cell lines, when compared to
APOE e3-expressing cells, excess production of IL6, IL10, and
nitrous oxide results from a failure to inhibit NF-κB (31). These
findings are replicated in neural cells and fibroblasts from AD
patients where APOE e4 acts as a transcription factor responsible
for regulating NF-κB expression (32). Curiously, cells from the
somatosensory cortex of AD patients, an area of the brain that is
resistant to disease, display upregulation of NF-κB (33). However,
this may reflect the earliest inflammatory hallmark of disease as
previous autopsy studies have shown increased NF-κB activation
in evolving Aβ deposits with a reduction in areas surrounding
more mature plaques (19, 33).
3. Figure 1 | The Toll pathway in fruit fly and the Toll-like receptor (TLR) 4 pathway in the mouse. (A) The Toll pathway in Drosophila melanogaster detects Gram-
positive bacteria and fungi is activated through an endogenous ligand, namely Nerve Growth Factor-related cytokine Spaetzle (SPZ) which is processed by Spaetzle-
processing enzyme (SPE). Toll receptor activation results in the recruitment of the adaptor proteins namely myeloid differentiation primary response 88 (dMyD88),
Tube, and Pelle, which promotes signaling to Cactus and its ankyrin-repeat domains. Cactus is bound to the nuclear factor-kappa B (NF-κB) transcription factors
dorsal-related immunity factor (DIF) and Dorsal and following activation of the pathway, it is phosphorylated and degraded. The above signaling events result in the
nuclear translocation of DIF or Dorsal that stimulate the transcriptional upregulation of antimicrobial peptide (AMP) genes, such as Drosomycin. (B). TLR4 receptor in
M. musculus detects lipopolysaccharides (LPS) from Gram-negative bacteria. Myeloid differentiation primary response 88 (MyD88) is recruited with Interleukin-1
receptor-associated kinases 1 and 4 (IRAK1, IRAK4), receptor-interacting protein 1 (RIP1), and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6).
TRAF6 is self-ubiquitinated in order to recruit transforming growth factor beta (TGF-β) activated kinase 1 (TAK1) and TAK1-associated binding proteins 1 and 2
(TAB1 and TAB2). The latter leads to the activation of the IκB kinase (IKK) complex that in turns phosphorylates the inhibitor of NF-κB (IκB). This leads to the release
of NF-κB that translocates to the nucleus and initiates the transcriptional induction of inflammatory and immune response related genes. This leads to the
translocation of the NF-κB transcription factors p50 and p65 to the nucleus, which in turns initiates the transcriptional induction of inflammatory and immune
response related genes.
3
Jones and Kounatidis NF-κB and Alzheimer Disease
Frontiers in Immunology | www.frontiersin.org December 2017 | Volume 8 | Article 1805
Invertebrate Models
A genetic screen for dominant suppressors and enhancers in a
Drosophila model of Aβ-driven neurodegeneration revealed
that Toll gene (receptor of Drosophila toll pathway) and key
downstream components (dif, pelle, cactus), play a central role
in mediating the neuropathological activities (34). Conversely,
genetic overexpression results in accelerated deterioration of
the phenotype suggesting that NF-κB significantly enhances the
pathological potential of Aβ (35).
Genetic suppression of the immune deficiency (IMD) NF-κB
pathway in glial cells in a Drosophila model of early onset neu-
rodegeneration dramatically rescues brain pathology, reduced
activity, and short lifespan (13). Genetic overexpression of NF-κB
pathways at neuronal or glial tissue level leads to phenotypes
resembling AD models with locomotor disability, accelerated
neurodegeneration, and premature mortality (13).
Vertebrate Models
Age is the biggest risk factor for dementia and systemic
inflammation increases as animal’s age, a process known as
inflammaging (36). Microglia priming in mice induces a highly
conserved transcriptional signature with aging characterized
by NF-κB expression and neuronal death (37). In rats, NF-κB
expression increases in normal aging leading to production of
neurodegenerative pro-inflammatory enzymes COX-2 and iNOS
(38). These changes are reversed by suppression of brain NF-κB
activation using the anti-inflammatory Lactobacillus pentosus
var. plantarum C29, restoring brain-derived neurotrophic factor
(BDNF) levels and memory (39). In mice, the observed positive
correlation between NF-κB activity and neuronal apoptosis
suggests a role of NF-κB in hippocampal neuroapoptosis (40).
Supporting this, NF-κB induces pro-apoptotic increases in TNF
and iNOS in the hippocampus of rats exposed to neurotoxin (41).
Inactivating specific Sirtuin anti-aging genes in mice results in
chronic NF-κB overexpression leading to accelerated aging and
dramatically reduced lifespan (23). In Sirtuin replete models,
overexpression via biofeedback dysregulation results in prema-
ture aging through chronic production of excessive ROS, leading
to telomere dysfunction, cellular senescence, and premature
death (42). Age-related NF-κB activation feeds into a positive
4. Figure 2 | The immune deficiency (IMD) pathway in fruit fly and the TNF pathway in the mouse. (A) The IMD pathway in Drosophila melanogaster is activated by
Gram-negative bacteria and certain Gram-positive bacilli. The intracellular adaptor protein immune deficiency (Imd) interacts with the Drosophila Fas-associated
death domain (dFADD) and the death-related ced-3/Nedd2-like caspase (DREDD) that cleaves Imd, which is then activated by K63 ubiquitination. This leads to the
activation of the transforming growth factor beta activated kinase 1 (TAK1) that in turn activates the D. melanogaster inhibitor of kinase kinase ß and γ complex
(dmIKKßγ). Activation results in the translocation of the nuclear factor-kappa B (NF-κB) transcription factor Relish (Rel) Dorsal to the nucleus which induces the
transcription of antimicrobial peptide (AMP) genes, such as Diptericin. (B) The tumor necrosis factor (TNF) pathway in M. musculus is activated by TNF alpha
(TNF-α) which binds and activates the transmembrane receptors R1 (TNFR1) and recruits the receptor-interacting protein (RIP) and TNF receptor-associated factor 2
(TRAF2). TRAF2 employs mitogen-activated protein kinase kinase kinase 3 (MEKK3) which in turn activates the inhibitor of kinase kinase ß and γ complex (IKKßγ),
which results to the translocation of NF-κB transcription factors p50 and Rel A. The latter translocation induces expression of several genes that are involved to
immunity and inflammation.
4
Jones and Kounatidis NF-κB and Alzheimer Disease
Frontiers in Immunology | www.frontiersin.org December 2017 | Volume 8 | Article 1805
feedback loop in microglial cells causing perpetual inflammation
and multiple brain responses including epigenetic suppression
of GnRH genes in the hypothalamus (14). Microglial-derived
NF-κB-TNF-α axis plays a key role in homeostatic synaptic
scaling, a form of synaptic plasticity. However, overexpression
results in disrupted neuronal networks and behavior mimicking
obsessive–compulsive disorder (OCD) (43, 44). Suppressing this
pathway mediates some of the OCD-like behavioral problems
in mouse models of frontotemporal dementia (44). Specifically,
under-expression of NF-κB in the mouse brain results in delayed
onset of age-related pathology across all organ systems via pres-
ervation of the hypothalamic–pituitary–adrenal axis and GnRH
levels (14).
ENVIRONMENT
Neuronal Cell Lines/Human Autopsy
Studies
Type 2 diabetes mellitus (T2DM), a metabolic condition charac-
terized by a decrease in sensitivity to endogenous insulin, is the
best established environmental risk factor for the development
of AD, increasing relative risk by 50% (45). Diabetes induces Aβ
pathology via NF-κB upregulation and independent overexpres-
sion of BACE1 (46, 47). Inflammatory mediators are known to
contribute to insulin resistance creating a pro-inflammatory
feedback loop in diabetes (48). Administering advanced glyca-
tion end products that mimic diabetic driven pathology results
in elevated BACE1 and consequent NF-κB overexpression in
both rat brains in vivo and neuroblastoma cells lines (49). NF-κB
suppression using Adiponectin rescues Aβ pathology in human
T2DM neuroblastoma cells (50). Similarly, leukotriene D4, an
inflammatory signaling molecule elevated in metabolic disorders,
induces Aβ synthesis in primary neurons at 24 h with increases in
NF-κB seen after just 1 h (51, 52). Treatment of the culture with
NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) inhibited
Aβ generation with down regulation of Aβ generating beta- and
gamma-secretase activity suggesting NF-κB regulates Aβ synthe-
sis in metabolic disease (52).
In human neuroblastoma cells, the metabolic enzyme protein
arginine methyltransferase 5 (PRMT5) regulates cellular metabo-
lism, protecting the cell in times of stress. Aβ downregulates this
process leading to NF-κB overexpression, metabolic dysfunc-
tion, and premature cell death (53). Inhibiting NF-κB reduces
5. 5
Jones and Kounatidis NF-κB and Alzheimer Disease
Frontiers in Immunology | www.frontiersin.org December 2017 | Volume 8 | Article 1805
apoptosis and Aβ deposits even in a metabolically dysfunctional
organism or human cell lines suggesting a gatekeeper role for
NF-κB in maintaining metabolic homeostasis and subsequent
neuroprotection independent of PRMT5 activity (53).
Invertebrate Models
In Drosophila models of chronic diseases including AD, the
innate immune system has been identified as a key mediator of
neurodegeneration (13, 34, 54, 55). NF-κB overexpression in the
fat body cells, analogous to the metabolic syndrome in humans,
results in more severe neurodegeneration (56).
Supporting the role of NF-κB in connecting whole-body
metabolism with brain health, NF-κB overexpression in the
hypothalamus-like pars intercerebralis neurons in Drosophila
results in overnutrition, impaired metabolic learning, poor
memory consolidation, and metabolic disorder characterized
by increased lipid levels and shortened lifespan (57). Conversely,
genetic knockdown of NF-κB signaling in glial cells leads to
elevated adipokinetic and glucagon-like hormone levels, reduced
glucose and lipid levels, and extension of “healthspan” (13).
Vertebrate Models
In rodent and primate models, diabetes and obesity drive over-
expression of NF-κB in the hypothalamus creating a destructive
feedback loop where further NF-κB expression promotes hyper-
tension, overnutrition, and decreased insulin sensitivity (58–61).
Injecting Aβ into the brains of mice and macaques results in an
increase in NF-κB in the cell nuclei of the hypothalamus and
subsequent induction of peripheral glucose intolerance (62). In
this model, pharmacological inhibition of NF-κB maintained
peripheral metabolic homeostasis. Inducing diabetes in rats
results in hippocampal NF-κB-dependent neurodegeneration via
disruption of CREB phosphorylation, reducing levels of protec-
tive downstream proteins including BDNF (63).
The tetracycline derivative Minocycline inhibits NF-κB and
prevents further Aβ deposition in a mouse model of diabetes-
driven AD. BACE1 activity remained elevated demonstrating
an NF-κB-dependent protective mechanism (29). Mice fed on
high-fat diets demonstrate elevated brain BACE1 expression as
do transgenic diabetic mice. Administration of the anti-inflam-
matory agent all-trans-retinoic acid reduces BACE1 expression in
both WT and mutant but this effect is abolished when the NF-κB-
binding site at the promoter region of BACE1 is mutated (64).
EMERGING RISK FACTORS
Alcohol Intake
In Drosophila, alcohol consumption activates Toll-NF-κB sign-
aling increasing ethanol resistance and gene products known
to be outputs of innate immune signaling are rapidly induced
following ethanol exposure (65). Ethanol treatment of cultured
hippocampal rat neurons causes a dose- and time-dependent
increase in NF-κB-DNA-binding activity, resulting in sig-
nificant upregulation of inflammatory markers and increased
susceptibility to neurotoxins; reversible by applying NF-κB
inhibitors (66, 67).
Opposing, the consumption of moderate amounts of alcohol,
particularly red wine, is associated with a reduced risk of AD.
Anthocyanin, a polyphenol found in wines, protects rat hip-
pocampal neurons against oxidative stress via NF-κB suppression
(41, 68).
Sleep
Sleep quality and well-being are symbiotic and reduced sleep
quality is increasingly being associated with increased risk of
dementia. Sleep–wake cycle homeostasis is important in the
processing and removal of Aβ plaques which, in turn, are known
to dysregulate this reparative process (69). Sleep disruption and
deprivation are known to cause over expression of the NF-κB
pathway in hippocampal cell cultures, fruit flies, rodents, and
humans (70–73). Improvement in sleep quality in older adults is
correlated with a reduction in circulating NF-κB (74).
Traumatic Brain Injury (TBI)
Traumatic brain injury activates both microglia and astrocytes
and induces self-sustaining inflammatory responses in the brain
via NF-κB activation (75, 76). In Drosophila, flies with TBI
exhibited temporary incapacitation, ataxia, activation of the
innate immune response, neurodegeneration, and death similar
to humans with TBI (77, 78). Rat models have demonstrated the
acute onset and prolonged overexpression of NF-κB in brain
regions most commonly associated with post-injury atrophy (79,
80). Recent studies have shown NF-κB to be significantly elevated
in the ipsi-lateral cortex of both adult and old TBI mice in a time-
dependent manner (81). These interactions started immediately
post-injury in the old mice compared to the adult mice suggesting
an age-related failure of NF-κB suppression.
PROTECTIVE FACTORS
Exercise
Under expressing NF-κB in mice results in greater endurance,
cognitive performance, and resistance to obesity (82). An aerobic
exercise protocol in wild-type rats attenuated age-related memory
decline and decreased hippocampal NF-κB levels and atrophy
(83). In rats fed a pro-inflammatory diet and subjected to either
strength training, aerobic exercise or a combination of both, all
protocols reduced liver and muscle NF-κB levels to pre-diet levels
(84). These findings are supported by studies demonstrating the
indirect suppression of NF-κB via cytokine IL-10, a potent NF-κB
inhibitor, induced by exercise (85).
Diet
Curcumin, a constituent of turmeric, has gained much attention
in recent years for its potential as a neuroprotective compound. In
a Drosophila model of neurodegeneration, the curcumin analog
C150 significantly reduced neuronal cell death, increased healthy
lifespan, and reduced DNA mutation in brain tissue by suppress-
ing NF-κB (86).
The neuroprotective effects resulting from the Mediterranean
diet or those rich in oily fish may be mediated via the anti-inflam-
matory properties of key nutrients (87). Aβ induced increases in
the translocation NF-κB subunits is attenuated in the presence of
6. 6
Jones and Kounatidis NF-κB and Alzheimer Disease
Frontiers in Immunology | www.frontiersin.org December 2017 | Volume 8 | Article 1805
tyrosol (Tyr) and hydroxytyrosol (OH-Tyr) found abundantly in
olive oil (88). Transgenic increases in omega-3 polyunsaturated
fatty acid in the brain of mice reduces the inflammatory response
to LPS challenge via NF-κB pathways (89).
The omega 3 fatty acid eicosapentaenoic acid indirectly
downregulates NF-κB expression acting as a ligand at peroxisome
proliferator-activated receptor gamma, a regulator of fatty acid
storage and glucose metabolism, and reduces symptoms of depres-
sion (87, 90). In AD-mouse hippocampal slices, food-derived
anti-oxidants provide neuroprotection and reduce Aβ via the anti-
inflammatory properties of the polyphenolic compounds within
them(91).Specifically,thephenoliccompoundresveratrolreduces
Aβ-induced migroglial activity and neuroinflammation via NF-κB
suppression in murine microglial and macrophage cells (92).
Anti-inflammatory Drugs
The prolonged use of non-steroidal anti-inflammatory drugs
(NSAIDs) is associated with a reduction in the AD risk (93). In
primary rat, neurons and human neuronal cell lines NSAIDs
strongly inhibit NF-κB-driven expression of BACE1 activity
preventing the cleavage of Aβ from APP (28, 94). Long-term
administration of potent NSAID indomethacin blocks activation
of NF-κB and significantly reduced the amyloid pathology in
transgenic AD mice (95).
Aspirin, an NSAID derived from salicylic acid, completely
inhibits Aβ activation of the NF-κB pathway, reducing levels
of pro-inflammatory cytokines and chemokines, and increas-
ing levels of anti-inflammatory IL-10 in rodent microglia and
neurons resulting in recruitment of Aβ phagocytic microglia and
improved cognitive and synaptic functioning (28, 96).
CONCLUSION
Epidemiological studies are beginning to converge of common
risk factors for the development of AD with strong signals also
emerging for certain protective factors. The emergence of NF-κB
as a regulator of aging and proliferation of studies implicating
NF-κB over-activation in a number of neurodegenerative dis-
eases suggests that it may be important in modulating the risk
of disease. This review has highlighted the intimate relationship
between all known and emerging risk and protective factors for
Alzheimer’s and NF-κB activity, implicating over-activation with
an increased risk of the disease and suppression being associated
with risk reduction. Future work, both in models of disease and
trials in man, should focus on therapies that directly target NF-κB
overexpression to explore whether early risk identification and
targeted anti-inflammatory treatment can significantly increase
the time of disease onset and, consequently, reduce the incidence
of this devastating disease.
AUTHOR CONTRIBUTIONS
SJ and IK wrote the manuscript, and IK designed the figures.
FUNDING
This work was supported by Consolidator Grant 310912 (Droso-
parasite) from the European Research Council to Prof. Petros
Ligoxygakis and by funding from the National Institute for Social
Care and Health Research.
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