Neuropathies

Microglial Priming in Alzheimer’s Disease

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Alzheimer’s disease (AD) is one of the most common types of dementia among older adults. Research studies have demonstrated that pathological changes in the human brain, whether directly or indirectly, can ultimately cause loss of synaptic function, mitochondrial damage, microglial cell activation, and neuronal cell death. However, the pathogenesis of AD is not yet fully understood and there is currently no definitive treatment for the neurological disease. Research studies have demonstrated that the activation and priming of microglial cells may contribute to the pathogenesis of AD. Β 

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A proinflammatory status of the central nervous system (CNS) can also cause changes in the function of the microglial cells or microglia. Neuroinflammation is closely associated with the activation of microglia and astrocytes which are connected to a variety of neurological diseases by the synthesis and secretion of inflammatory mediators such as iNOS, ROS, and proinflammatory cytokines. According to research studies, microglial priming is also caused by the inflammation of the CNS.

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Therefore, whether microglial priming is the result or the cause of neuroinflammation is still controversial. Microglial cell activation commonly causes an increase of A? and tau proteins as well as a decrease of neurotrophic factors, ultimately leading to the loss of healthy brain cells or neurons and the development of neuritic plaques and neurofibrillary tangles which are closely associated with AD. With the progression of Alzheimer’s disease, changes from neuronal dysfunctions which may have no obvious symptoms to memory loss and cognitive impairment may become more noticeable. Β 

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Microglial Priming, Neuroinflammation, and AD

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Although the accurate and detailed, fundamental role of the microglial cells continues to be discovered and explained, there is a consensus among many researchers that primed microglia are associated with the inflammatory response of the CNS in AD. It has also been determined that neuroinflammation caused by microglial priming is mainly associated with aging, systemic inflammation, gene regulation, and blood-brain barrier impairment. The purpose of the article below is to discuss how microglial priming and neuroinflammation in Alzheimer’s disease can be caused due to a variety of risk factors.

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Aging

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Aging is considered to be one of the main risk factors for AD and it is generally followed by chronic, systemic up-regulation of pro-inflammatory factors and a considerable decrease in an anti-inflammatory response. This change from homeostasis to an inflammatory state occurs through age-related elements which cause an imbalance between anti-inflammatory and pro-inflammatory systems. Microglia is primed into an activated state which can increase the consistent neuroinflammation and inflammatory reactivity in the aged human brain. Research studies have demonstrated that microglia in the brain of rodents developed an activated phenotype during aging characterized by the increased expression of CD11b, CD11c, and CD68. Β 

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Systemic Inflammation

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Recent research studies have determined that the neuroinflammation from primed microglial cells can also cause the pathogenesis of AD. Continuous activation of microglia can promote the synthesis and secretion of pro-inflammatory cytokines and trigger a pro-inflammatory response, ultimately causing neuronal damage. Neuroinflammation is an early symptom in the progression of AD. The microglia can have a tremendous effect on the inflammation of the human brain.

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The inflammation and health issues of the CNS can be associated with systemic inflammation through molecular pathways. One research study demonstrated that ROS development of primed microglia decreases the levels of intracellular glutathione and increases nitric oxide in NADPH oxidase subunit NOX2. Moreover, researchers demonstrated that these simultaneously occurring processes ultimately cause the development of more neurotoxic peroxynitrite. This is demonstrated in rodents with peripheral LPS or proinflammatory cytokines, such as TNF-?, IL-1?, and IL-6, IL-33.

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The outcome measures of numerous research studies have demonstrated that systemic inflammation can cause microglial activation. The results of the research studies emphasize the variability of the inflammatory response in the human brain associated with AD and the underlying health issues associated with systemic inflammation and neuroinflammation, as shown in Table 1. MAPK (mitogen-activated protein kinase) signaling pathways regulate mechanisms of the eukaryotic cell and microglial MAPK can also cause an inflammatory response to the aged brain with AD. Furthermore, chronic or continuous systemic inflammation causes neuroinflammation, resulting in the onset and accelerating the progression of AD. Β 

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Genetic Regulation

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In the aging human brain, gene regulation has ultimately been associated with an innate immune response. Recent preclinical, bioinformatics, and genetic data have demonstrated that the activation of the brain immune system is associated with the pathology of AD and causes the pathogenesis of this neurological disease. Genome-wide association studies (GWAS), functional genomics, and even proteomic evaluations of cerebrospinal fluid (CSF) and blood have demonstrated that dysfunctional immune pathways from genic mutation are risk factors in LOAD, which is the vast majority of AD.

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GWAS have become a fundamental tool in the screening of genes as well as demonstrating several new risk genes associated with AD. Apolipoprotein E (APOE) ?4allele is one of the most considerable and well-known risk genes for sporadic AD and this mutation ultimately increases the risk of neurological disease onset by 15 times in homozygous carriers and by three times in heterozygous carriers. Further research studies have demonstrated how microglial cell function can be affected through a variety of rare mutations which have demonstrated to have an increased risk factor of Alzheimer’s disease.

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An extracellular domain mutation of the TREM2 gene has also demonstrated an almost identical extent with APOE?4 in increasing the risk factor of AD. TREM2 is increasingly demonstrated on the surface of microglia and mediates phagocytosis as well as the removal of neuronal debris. Additionally, several other genes, such as PICALM, Bin1, CLU, CR1, MS4A, and CD33 have been demonstrated as risk genes for AD. Most of the risk mutation genes are expressed by microglial cells. Β 

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Blood-Brain Barrier (BBB) Impairment

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The blood-brain barrier (BBB) is a specialized barrier commonly developed between the blood and the brain by tight liner sheets consisting of specific endothelial cells and tight junctions or structures which connects a variety of cells together. The CNS is fundamental for the human body, and the BBB is fundamental for the CNS. The BBB and the blood-nerve barrier develop a defense system to control the communications of cells and soluble factors between blood and neural tissue where it plays a considerable role in maintaining and regulating the homeostasis of the CNS and peripheral nervous system.

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With development, continuous inflammation can also cause damage to the BBB. This damage can ultimately cause loss of hypersensitive neurons, neuroinflammatory regions, and focal white matter impairment following the damage. The compromised BBB also allows more leukocytes to enter into the CNS where an immune response can be aggravated by brain microglia under the condition of peripheral inflammation. These processes may ultimately be under the control of chemokine and cytokine signaling which can also have an effect on brain microglial cells as well as other health issues in AD.

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By way of instance, it has been determined that TNF-?, IL-17A, and IL-1? can reduce the tight junctions and eliminate the BBB. Loss of BBB integrity and abnormal expression of tight junctions are associated with neuroinflammation. Several research studies also demonstrated in an animal model of AD that the vulnerability of BBB to inflammation increases. Current evidence has also demonstrated that the BBB integrity is fundamental while further evidence of the BBB may demonstrate a new treatment approach for AD associated with microglial priming as shown in Figure 2 below. Β 

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Conclusion

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Microglia play a fundamental role in maintaining and regulating the homeostasis of the CNS’s micro-environment. If the balance of the homeostasis of the human brain is interrupted, the microglial cells can be activated to restore the balance in the CNS by defending against the stimulation and protecting the structure and function of the brain. However, chronic and continuous stimulation can trigger microglia into a state known as microglial priming, which is more sensitive to potentially minor stimulation, causing a variety of health issues, such as central sensitization, chronic pain, and fibromyalgia.

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Microglial priming mainly causes the boost of A?, tau protein as well as neuroinflammation and reduces neurotrophic factors which can cause the loss of healthy brain cells or neurons as well as the development of neuritic plaques and neurofibrillary tangles which are associated with Alzheimer’s disease. Although this β€œdouble-edged sword” plays a fundamental role, it can increase the progression of abnormal protein development and aggravate neuronal loss and dysfunction. However, research studies have ultimately demonstrated that aging can cause the progression of AD and there’s not much we can do about it.

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Microglial cells play a fundamental role as the protectors of the brain and they ultimately help maintain as well as regulate the homeostasis of the CNS microenvironment. However, continuous stimulation can cause the microglia to trigger and activate at a much stronger state which is known as microglial priming. Once the microglial cells go into protective mode, however, primed microglia can become much more sensitive to even minor stimulation and they have a much stronger possibility of reacting towards normal cells. Microglial priming has been associated with neuroinflammation and Alzheimer’s disease (AD) as well as central sensitization and fibromyalgia. – Dr. Alex Jimenez D.C., C.C.S.T. Insight

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Neuropathy Treatment with LLLT

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AD is one of the most common types of dementia among older adults. However, the pathogenesis of AD is misunderstood and there is no definitive treatment for the neurological disease. Research studies have ultimately demonstrated that the activation and priming of microglial cells may contribute to the pathogenesis of AD. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . Β 

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Curated by Dr. Alex Jimenez Β 

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Additional Topic Discussion: Chronic Pain

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Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.

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Neural Zoomer Plus for Neurological Disease

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Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual’s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. Β 

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Formulas for Methylation Support

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If you are a patient of Injury Medical & ChiropracticΒ Clinic, you may inquire about XYMOGEN by calling 915-850-0900.

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Post Disclaimer

Professional Scope of Practice *

The information herein on "Microglial Priming in Alzheimer's Disease" is not intended to replace a one-on-one relationship with a qualified health care professional or licensed physician and is not medical advice. We encourage you to make healthcare decisions based on your research and partnership with a qualified healthcare professional.

Blog Information & Scope Discussions

Our information scope is limited to Chiropractic, musculoskeletal, acupuncture, physical medicines, wellness, contributing etiological viscerosomatic disturbances within clinical presentations, associated somatovisceral reflex clinical dynamics, subluxation complexes, sensitive health issues, and/or functional medicine articles, topics, and discussions.

We provide and present clinical collaboration with specialists from various disciplines. Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the injuries or disorders of the musculoskeletal system.

Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate to and directly or indirectly support our clinical scope of practice.*

Our office has reasonably attempted to provide supportive citations and has identified the relevant research studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request.

We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez, DC, or contact us at 915-850-0900.

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Dr. Alex Jimenez DC, MSACP, RN*, CCST, IFMCP*, CIFM*, ATN*

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