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Beta Xb For Alzheimer’s

Ca2+ Increases The Production Of Proinflammatory Cytokines

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Neuroinflammation is widely accepted to be mediated by Ca2+ dyshomeostasis and induces the cognitive decline associated with AD. This process is studied to understand the inherent mechanisms by which Ca2+ exerts an effect. For example, Ca2+ increases the production of interleukin -1 and tumor necrosis factor via calcineurin in glial cells . Consistently, an indirect blockade of Ca2+ entry into lipopolysaccharide -activated microglia stimulates the production of proinflammatory cytokines, such as TNF- and IL-6 . These observations revealed critical roles for Ca2+ in inducing neuroinflammation by concurrently increasing the production of proinflammatory cytokines and decreasing the levels of anti-inflammatory cytokines.

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The key therapy against AD is based on the application of centrally acting AChE inhibitors to compensate for the cholinergic deficit in the brain. AChE is found primarily in the blood and in the neural synapses, and has been shown to be the most viable therapeutic target to improve the symptoms of AD. In addition to AChE, the liver contains butyrylcholinesterase . Most of the available drugs for the treatment of AD target both AChE and BuChE however, some of them are more selective than others. Historically, the first ChEI was the alkaloid, physostigmine, isolated from the seeds of Physostigma venenosum, but the drug exhibited many side effects and was accordingly abandoned for the treatment of AD . Tacrine was the first drug approved for the treatment of AD, and was introduced in 1993 however, due to its various side effects, its widespread application was limited and a series of new drugs were approved after 1995, including donepezil, rivastigmine and galantamine.

Fig. 2

Docking calculations revealed that the scutellarin functionality protrudes out of the cavity gorge, while the tacrine functionality interacts with the CAS of AChE. A similar stereochemical orientation has also been reported for tacrinetianeptine or 7-methoxytacrineadamantylamine hybrids . An opposite arrangement, in which tacrine interacts with PAS has been reported for 7-methoxytacrinep-anisidine , 7-methoxytacrinedonepezil and tacrinetrolox heterodimers .

Brain Insulin Resistance And Insulin Deficiency

Type 2 diabetes mellitus is a risk factor for AD and these two disorders share many common pathological pathways. Impaired glucose metabolism is related to rising oxidative stress and accumulated advanced glycation end products. Insulin is even produced in brain tissue itself. Insulin receptors are mostly located in the cerebral cortex, cerebellum, hypothalamus, hippocampus and olfactory bulb that are the cognition pertinent areas of the brain. Brain glucose utilization and insulin signaling are impaired in AD. AD is related to a reduction in the levels of insulin in the cerebrospinal fluid , in the ratio of CSF insulin/plasma insulin, a decline in the expression of insulin receptors and a rise in fasting plasma insulin levels. Impaired insulin signaling might influence AD pathogenesis via tau hyperphosphorylation, acetylcholine signaling and A metabolism. Insulin stimulates the expression of choline acetyltransferase, the enzyme responsible for acetylcholine synthesis. Therefore, decreased insulin levels, as well as insulin resistance, can ultimately contribute to a decrease in acetylcholine in AD brains .

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Advantages Of Dna Vaccines Over Conventional Peptide/protein Vaccines

DNA-based vaccination utilizes direct injection of plasmid DNA encoding genes for protein or peptide antigens. The facilitated uptake of the DNA by cells that then express the antigen, which when encountered by cells of the immune system provokes an immune response against expressed antigen . DNA vaccination is currently being used for the development of vaccines against a variety of pathogens, as well as for human diseases including cancer, autoimmune disorders, and AD. A unique property of DNA-based vaccination is the ability to induce prolonged, endogenous antigen synthesis and processing within the immunized host own cells. DNA immunization has been shown to generate protective humoral and cellular immune responses against viral, tumor, and foreign antigens . Among many significant advantages of DNA immunization are less complicated technologies of production, high stability, the capability to modify genes encoding the desired antigen/s, the ability to make changes in the cellular localization of an antigen by means of adding or removing signal sequences or transmembrane domains and the ability to target the desired type of immune response to enhance the therapeutic potential of the immune response. The immune response to DNA immunization can be enhanced by using molecular adjuvants , such as cytokines in conjunction with the immunogen, which can direct the T helper cell toward the desired pathway.

Future Therapeutic Approaches And Management Of Ad

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Alzheimers disease is one of the most challenging threats to the healthcare system. The current therapeutic goals are to reduce amyloid levels, prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. There is also a major improvement in understanding the role of cholinesterase in the brain and the function of ChE inhibitors in AD Academic research has carried out on the system of a new generation of acetyl- and butyryl ChE inhibitors and test for AD in clinical experiments on human beings. Next to this alternative strategies for treating or slowing the progression of AD, like vaccination, anti-inflammatory agents, cholesterol-lowering agents, antioxidants and hormone therapy, are also studied. Although several anti-amyloid compounds have been examined in clinical trials as potentially useful drugs, all of them have failed to show significant benefits so far. Tau-targeted drugs have been developed and have entered clinical trials recently. The improvements on early diagnostic biochemical markers will be useful to increase for better monitoring the course of the disease and to evaluate different therapeutic strategies .

2.6.1 Anti-amyloid agents

2.6.2 Secretase modulators

2.6.3 Amyloid anti-aggregates

2.6.4 Amyloid removal

2.6.5 Tau-based therapies

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Insights From The First Immunotherapy Clinical Trial In Ad Patients

Additional problems that plagued the AN1792 trial were the low number of positive responders and the generally low titers. In all fairness, many of the patients in the clinical trial did not receive the full course of immunizations proposed in the AN1792 protocol. Moreover, based on results from the recent passive immunotherapy clinical trial using bapineuzumab, a humanized monoclonal antibody against the end terminus of A, higher titers may increase the risk of adverse events . During the Phase II study with bapineuzumab 12 cases of vasogenic edema were reported. The incidence of vasogenic edema was dose-dependent , and ApoE4 carriers were over-represented .

Another concern regarding the AN1792 clinical trial was the selection of QS21 as the adjuvant. While QS21 is a powerful adjuvant, the risk of adverse events due to immunization with strong Th1-type adjuvant in an elderly population in which there is already substantial parenchymal and cerebrovascular inflammation needs to be considered. In particular, the meningeal and cortical blood vessels in many AD patients have activated perivascular macrophages and astrocytes, which will become further activated by strong peripheral inflammatory events . There is even evidence that systemic inflammation that produces elevated levels of interleukin-1 in the CNS can contribute to cognitive decline in AD .

Alzheimers Diet: 16 Foods To Fight Dementia + What To Avoid

The best diet for Alzheimers is Dr. Bredesens KetoFLEX 12/3 diet, which is a keto diet mixed with metabolic flexibility. It encourages 12-hour fasting periods every day, including at least 3 hours of fasting before bedtime.

This slightly-flexible ketogenic diet can lower your risk of developing Alzheimers disease or dementia. In the earliest stages of mental decline, an Alzheimers diet may even reverse cognitive decline.

This revolutionary diet also encourages 12-hour fasting periods so the body has more time to repair cell damage. Make sure to not eat within 3 hours of going to bed either.

What are the benefits of an Alzheimers diet? The benefit of an Alzheimers diet is taking control of your own health, based on science. Eating foods like green leafy vegetables, fish, nuts, and even an occasional glass of red wine can reduce your chances of developing Alzheimers.

Can Alzheimers be reversed with diet? In the earliest stages of cognitive decline, adhering to an Alzheimers diet may reverse cognitive decline. Unfortunately, theres no surefire Alzheimers cure. However, we have personally observed patients whose cognitive decline was reversed after making specific lifestyle changes, including changing their diet.

Can dementia be reversed with diet? Advanced dementia cannot be reversed with a healthy diet. However, the KetoFLEX 12/3 diet shows promise in slowing general cognitive decline and early stages of dementia.

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Er Stress Induces Autophagy By Modulating The Dyshomeostasis Of Ca2+

Based on the aforementioned observations, InsP3R was found to connect mitochondria, potentially contributing to apoptosis and autophagy . In A-treated PC12 cells, moderate activation of autophagy regulates intracellular Ca2+ levels and the mitochondrial membrane potential . Reciprocally, mitochondrial fission-mediated Ca2+ signaling induces the expression of Stim1 and subsequent SOCE, which promoted autophagy through Ca2+/CAMKK/AMPK signaling cascades . Regarding Ca2+ transporters in mitochondria, VDAC recruits Parkin to defective mitochondria, resulting in the induction of mitochondrial autophagy in HEK293 cells . In addition, p53 is actively recruited to the outer membrane of mitochondria during nutrient deprivation, resulting in opening of the mPTP, an increase in the conversion of LC3BII to LC3BI, and the formation of LC3-GFP puncta in ventricular myocytes .

The Adjuvant Problem For Anti

Folding@home COVID-19 Work

The issue of selecting an appropriate adjuvant to amplify the immune response to produce therapeutic levels of anti-A antibodies in the elderly without triggering unacceptable adverse events is complicated by several factors. The first is that currently alum is the only approved adjuvant for human vaccines, and while alum is known to be good at inducing antibodies, it is not considered a very potent adjuvant, which may restrict its usefulness in an elderly population . Interestingly, we found alum to be quite an effective adjuvant for inducing therapeutic levels of anti-A antibodies, as measured by a reduction amyloid plaque load in all of the elderly canines that were immunized with fibrillar A bound to alum . Importantly, adjuvants can control the type of immune response generated against A-containing immunogens to alter the response toward either a Th1 or Th2 , which may be important in avoiding adverse events caused by elevated levels of various cytokines and chemokines, as well as the isotype of the antibodies that are generated in response to the vaccine immunogen. The isotype of the antibody determines the type of effector functions, such as activation of complement or Fc-receptor mediated activation of macrophages, that can be induced when the antibody binds its target antigen and forms an immune complex.

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Reduction Of A Generation

A is generated from proteolytic cleavage of APP through the amyloidogenic pathway . Under physiological conditions, APP is predominantly cleaved via the non-amyloidogenic pathway, which occurs by -secretase cleavage to generate the soluble APP fragment and the membrane-anchored C-terminal fragment C83. C83 is then cleaved by -secretase, resulting in the release of the nontoxic P3 fragment and CTF . APP can also be cleaved by -secretase at the Glu11 site or by -secretase to produce C89 and C80, respectively, precluding A generation . Alternatively, APP undergoes amyloidogenic cleavage by BACE1 at the Asp1 site to release sAPP and C99. Next, -secretase cleaves the C99 to release toxic A1-40 or A1-42 .

What Is Beta Hydroxybutyrate

The definition of beta hydroxybutyrate is a ketone body that is an intermediate product of the breakdown of fats in the body. Ketogenesis is considered the metabolism of fatty acids by -oxidation. BHB is one of three main ketone body compounds that are produced when someone is in the metabolic state of ketosis .

Normally, when someone eats a standard diet that includes various sources of carbohydrates, the main function of carbs is to provide fuel or energy for the body. In the absence of carbohydrates and when a depletion of glycogen occurs which is exactly what happens when someone follows the keto diet the liver makes ketones from fatty acids.

While carbohydrates are the bodys preferred fuel source and the first type of energy used to fuel physical and cellular activities, fat is also a fuel source. Usually we only need small amounts of dietary fat/essential fatty acids to maintain steady energy, but when following the keto diet the need for fat drastically increases.

Other situations in which BHB is produced is when someone fasts for around 16 hours or more. Since the body interprets fasting as a sign that energy intake is low, it increases ketone production in order to have another fuel source. The production of ketone bodies helps save any available glucose for the brain, which uses glucose quickly. When glucose is not available, fatty acids as well as ketone bodies can also be metabolized by the brain.

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About Dr Fred Pescatore

Fred Pescatore, MD, is one of the most sought-after natural physicians in the country, specializing in making you feel like the best version of you! And in his exclusive clinic in midtown Manhattan, Dr. Pescatore has been using a dementia-reversing therapy with tremendous success for .

You may have already met Dr. Pescatore on Good Morning America, The OReilly Factor, Rachael Ray, The Today Show, Extra, The View, and many more sharing the latest breakthroughs in integrative and nutritional medicine. Hes specifically been interviewed and requested as a keynote regarding his expertise in brain health many times.

Dr. Pescatore is the author of the New York Times best-selling book, The Hamptons Diet and the No. 1 best-selling childrens health book, Feed Your Kids Well, amongst others. Dr. Pescatores other books include: The A-List Diet, Thin For Good, The Allergy and Asthma Cure, The Hamptons Diet Cookbook and Boost Your Health with Bacteria.

Dr. Pescatore has his finger on the pulse of natural medicines most cutting-edge cures. As a result, everyone from normal hardworking Americans to international royalty are traveling hundreds of miles to visit at his renowned clinic in New York City.

Hes spent over 3 decades studying, researching and practicing medicine around the world alongside some of todays most well respected physicians.

Discuss With Your Doctor

Should you or a loved one take aducanumab? You should discuss this decision with your doctor. Because we dont know if aducanumab works or not, deciding to take it is similar to deciding to participate in a clinical trial. As mentioned above, the known side effects are that 30% of people experienced reversible brain swelling and more than 10% had tiny brain bleeds. Although it does clear amyloid plaques from the brain, we dont know if it will slow down the dementia or not.

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What Happens To The Brain In Alzheimer’s Disease

The healthy human brain contains tens of billions of neuronsspecialized cells that process and transmit information via electrical and chemical signals. They send messages between different parts of the brain, and from the brain to the muscles and organs of the body. Alzheimers disease disrupts this communication among neurons, resulting in loss of function and cell death.

Designing Epitope Vaccines Composed Of The N Terminal Region Of A42 And Foreign Promiscuous T Cell Epitope

Our first DNA construct to incorporate a molecular adjuvant into the design of the anti-A DNA epitope vaccine contained interleukin-4 . We generated a gene encoding human A42 fused with murine IL4 . Immunization of B6SJLF1 mice with this construct generated predominantly IgG1 and IgG2b anti-A42 antibodies . Both isotypes of anti-A antibodies bound to A1-15 epitope in an ELISA and were capable of binding to amyloid plaques in brain tissue from AD cases . Thus, we demonstrated that DNA immunization is capable of inducing Th2-type therapeutically potent anti-A42 antibodies in wild type mice. The pA42-IL4 prototype vaccine allowed us to break tolerance and induce primarily Th2-type IgG1 antibodies specific to the self-A42 antigen in APP-Tg2576 mice. DNA vaccination, however, induced significantly lower anti-A antibody production in APP-Tg2576 mice compared with wild-type animals . These results were not totally unexpected, because previously we and others reported that immune responses to A in APP-Tg2576 mice were significantly impaired even when protein immunizations with fA42 was used .

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How To Optimize Levels

The best way to naturally increase/optimize BHB levels is by eating a very-low carb, very high-fat diet . This can also be combined with intermittent fasting or other types of fasting to further boost ketone production. And to really increase BHB production and fat burning, you can combine a ketogenic diet, intermittent fasting and exogenous ketones like BHB salts.

Even when correctly following the keto diet, many people can also benefit from using ketone supplements although for the most payoff its best to alter your diet, leading to natural ketone production. Keep in mind that most low-carb diets will not lead to increased ketone levels only the ketogenic diet can effectively do this. How do you follow the ketogenic diet and stay in nutritional ketosis? In simplest terms, you need to get 70 percent to 80 percent of your daily calories from fat, no more than 20 percent to 25 percent of calories from protein and no more than 5 percent to 10 percent carbs of daily calories from carbohydrates.

What are the best beta hydroxybutyrate food sources for boosting levels?

Below are the best low-carb foods to eat regularly when following the ketogenic diet:

Whats the best BHB supplement/ketone supplement?

There are three main types of ketone supplements:

Key Biological Processes In The Brain

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Most neurons have three basic parts: a cell body, multiple dendrites, and an axon.

  • The cell body contains the nucleus, which houses the genetic blueprint that directs and regulates the cells activities.
  • Dendrites are branch-like structures that extend from the cell body and collect information from other neurons.
  • The axon is a cable-like structure at the end of the cell body opposite the dendrites and transmits messages to other neurons.

The function and survival of neurons depend on several key biological processes:

Neurons are a major player in the central nervous system, but other cell types are also key to healthy brain function. In fact, glial cells are by far the most numerous cells in the brain, outnumbering neurons by about 10 to 1. These cells, which come in various formssuch as microglia, astrocytes, and oligodendrocytessurround and support the function and healthy of neurons. For example, microglia protect neurons from physical and chemical damage and are responsible for clearing foreign substances and cellular debris from the brain. To carry out these functions, glial cells often collaborate with blood vessels in the brain. Together, glial and blood vessel cells regulate the delicate balance within the brain to ensure that it functions at its best.

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