Proteins Amyloid And Prions Oh My
A protein is made in a cell as a long, linear chain of building blocks, and interactions between these building blocks cause this chain to spontaneously fold into a specific three-dimensional shape. . The correct folding of a protein into this 3D shape is essential for its proper function. In some instances, proteins can misfold and clump together to form aggregates, which can be very toxic to normal, healthy cells. The clumping of specific proteins is associated with a variety of disorders, notably Alzheimers disease and fatal prion diseases, which include the livestock disorder bovine spongiform encephalopathy , as well as the human diseases, Kuru and Creutzfeldt-Jakob disease.
The protein-misfolding event that initially triggers the formation of amyloid aggregates in Alzheimers disease and in prion diseases is usually a spontaneous occurrence. It is known, however, that people can have certain inherited genetic mutations that can increase the likelihood of having these A or PrP protein clumps form . Prion diseases, however, are remarkable in that they are infectious and can be transmitted from one person to another .
Prp Sc And A42 Plaque Distribution
In most patients, PrP Sc was distributed either in all layers of the cortex or in deep layers 4 to 6. Rarely was the distribution of PrP Sc found in superficial layers 1 to 3. For cases in which PrP Sc was deposited in deeper cortical layers, such as an 81-year-old woman who was near the end of the age distribution for the Prion-AD group , A42 plaques tended to be distributed in superficial layers 1 to 3 . In another case of a 53-year-old woman who was at the beginning of the Prion-AD age distribution, PrP Sc staining was confined to layers 5 and 6 in the lateral frontal cortex and A42 plaques were located in layer 1 . In the parietal cortex of the same patient, PrP Sc accumulated in all 6 cortical layers , and A42-positive plaques were found in cortical layers 1 to 5 . This suggests that A42 plaques are first formed in layer 1 of the cerebral cortex and subsequently progress in order from layers 2 through 6.
Alzheimers An Infectious Disease
Editors Note: In April 2019, Dr. Stanley Prusiner published conclusive evidence that Alzheimers disease is a prion disease. The implications are far-reaching. Prion disease is highly infectious and fatal. It impacts 50-100 million victims, their family, friends and caregivers today. Its time to reform policies and practices on many fronts to protect public health and entire ecosystems.
If you think that you and your family are immune to the surging epidemic of neurodegenerative disease, think again. Neurodegenerative disease, including Alzheimers disease, is the fastest-growing cause of death in the world. Its getting worse every day thanks to mismanagement, misinformation and widespread contamination.
Death rates from heart disease and cancer are dropping in many countries due to advances in nutrition, medicine and disease management. Meanwhile, neurodegenerative disease is spreading exponentially. In the U.S., deaths attributed to Alzheimers disease increased 71 percent from 2000 to 2013, while those attributed to heart disease 14 percent. Experts suggest that the prevalence of this neurodegenerative disease will quadruple by 2050, if not sooner. Dementia is vastly undiagnosed and misdiagnosed. Unfortunately, doctors are withholding millions of additional diagnoses, so we dont know the extent of the epidemic.
Read Also: What Color Is The Dementia Ribbon
Ad: A Story Of Two Prions
Intracerebral injection of aggregation-prone mutant tau in mice has also been demonstrated to induce wild-type tau to form neurofibrillary tangles and spread throughout the brain . Accumulating evidence indicates that A works upstream of tau in AD pathogenesis . A can bind to tau and induce formation of tau oligomers, which can then self-propagate without additional A, indicating a cross talk between the two prions .
Prpc: A Novel Therapeutic Target For Ad
PrPC has been identified as a major player in mediating the toxicity of A oligomers that leads to synaptic loss and cognitive impairment in AD. Therefore, targeting PrPC, its interaction with A oligomers, or downstream mediators can be considered the new line of choice for therapeutic development for treatment of Alzheimer’s disease.
Genetic ablation of PrPC in mice rescues the neurotoxic phenotypes of A oligomers . It might be reasonable to speculate that using shRNA or siRNA to knock down the expression of PrPC may represent a therapeutic approach for AD, though little has been done in this regard. Nevertheless, knocking down PrPC will also affect other functions of PrPC, causing various complications. For example, PrPC reduces A production by inhibiting BACE1 activity, and has a protective role in AD . This can be jeopardized by PrPC knockdown.
Screening for small molecules that could efficiently target either the A oligomer/PrPC interaction or the downstream mediators may represent a promising avenue for therapeutic development.
The Fyn kinase has been found to be activated upon binding of A oligomers with PrPC, which then initiate downstream signaling to mediate A toxicity, for example, activation of Fyn kinase lead to hyperphosphorylation of tau . Targeting Fyn kinase or other A/PrPC downstream mediators, for example by genetic engineering, RNAi, or small molecule modulators, may also be of therapeutic value.
Also Check: Difference Between Senility And Dementia
Research Now Shows That Amyloid Plaques And Tau Tangles From Diseased Brains Can Infect Healthy Brain Tissue The Infectivity Of Brain Tissue Is Just The Tip Of The Iceberg
Prions invade the entire body, but they do their damage in the brain. Prions are in the bodily fluids and cell tissue of victims, including blood, saliva, mucus, urine and feces. Common household items become biohazards, including utensils and dishes. A cough or sneeze sends prions into the air. Prions are a real-world version of Pandoras Box. Prions are unstoppable. Prion disease is always fatal. This is an extremely important issue that demands the truth from government and industryespecially the medical world.
Prions migrate, mutate, multiply and kill with unparalleled efficiency. Containing prions and preventing their spread is the key to avoiding a public health disaster. Unfortunately, the floodgates have been wide open for years.
Prion disease also is known as transmissible spongiform encephalopathy . The operative word is transmissible. Prusiner claims that all forms of TSE are caused by infectious prions. TSE is a spectrum disease that varies in severity and symptoms. The diagnosis depends on which region of the brain is impacted first and by what prion mutation. Few cases are identical in terms of symptoms and diagnoses.
Prions are such a formidable threat that the U.S. governmentenacted the Bioterrorism Preparedness and Response Act of 2002, which includeda provision to halt research on prions in all but two laboratories.
What Does This Project Involve
The researchers have previously recruited 50 people with a genetic risk of prion disease into a study that monitors their health over time. The researchers will take samples of spinal fluid every year from the participants and will examine whether there is any toxic prion protein present in the samples. This will be compared to spinal fluid taken from people who do not have a genetic link to prion diseases. The researchers will continue to assess the participants over time and will understand whether the appearance of toxic prion proteins in the spinal fluid is a reliable indicator of early disease onset.
Also Check: Neurotransmitters Associated With Alzheimer’s Disease
Scjd Induces H In Hu Brnaggs
Untreated Hu BrnAggs produced large bands of tau . Exposure to a normal brain homogenate produced smaller bands and 2 very weak bands . Exposure to sCJD produced bands between 40 and 50 kDa and strong bands of phosphorylated tau .
In another preliminary study, we made BrnAggs from transgenic mice expressing human mutated tau. These mouse tau BrnAggs spontaneously form small numbers of neurons containing H in nerve cell bodies and dendrites. When Mo BrnAggs were exposed to an A42-containing homogenate from a transgenic 2576 mouse, the number of neurons containing abnormal tau increased approximately 2-fold. In contrast, when tau BrnAggs were exposed to a brain homogenate from a wild-type mouse infected with Rocky Mountain Laboratories scrapie prions containing PrP Sc , the number of neurons and their processes containing abnormal tau increased 10-fold. These results were reproduced in triplicate. The findings argue that exposure to A42 and PrP Sc increases the levels of H inclusions in tau BrnAggs. We did not use normal age-matched human brain homogenate controls in these studies, which is why we classified them as preliminary .
Researchers Find New Hints That Could Explain How The Disease Spreads In Human Brains
Case Western Reserve University researchers studying human prionsmisfolded proteins that cause lethal and incurable diseaseshave, for the first time, identified surface features responsible for the replication of prions in the brain.
The ultimate goal of their research is to design a strategy to stop prion disease in humansand, ultimately, to translate new approaches to work on Alzheimers and other neurodegenerative diseases.
Scientists have yet to discover the exact cause of Alzheimers disease, but largely agree that protein issues play a role in its emergence and progression. Alzheimers disease afflicts more than 6 million people in the U.S., and the Alzheimers Association estimates that their care will cost an estimated $355 billion this year.
Research was done at the Safar Laboratory in the Department of Pathology and the Center for Proteomics and Bioinformatics at Case Western Reserve University School of Medicine, and at Case Western Reserves Center for Synchrotron Bioscience at Brookhaven Laboratories in New York. Jiri Safar, professor of pathology, neurology and neurosciences at Case Western Reserve University School of Medicine, leads the work. The report, Structurally distinct external domains drive replication of major human prions, was published in the June 17 issue of PLOS Pathogens.
The researchers developed a new three-step process to study human prions:
Recommended Reading: Smelling Farts Prevents Cancer
The Spreading Confusion: Rethinking Alzheimers Disease
Proteins are molecular machines. They perform an incredible diversity of tasks that enable all living cells to function. Like any machine, a protein must be properly assembled in order to carry out its specific task, and if something goes awry, the cellular consequences can be dire. Take Alzheimers disease for example. Alzheimers disease is the most common neurodegenerative disorder, affecting over 5 million people in the United States alone . Alzheimers is a progressive disorder that manifests clinically as a loss of memory, personality traits, and the ability to carry out daily tasks . Scientists do not fully understand why or how this disease develops, but it is known that in the brains of Alzheimers patients, some of these protein machines malfunction, forming large, toxic clumps. A major goal of Alzheimers research has been to uncover the causes and understand the consequences of this protein clumping. A recent study published in the journal Nature draws an interesting parallel between Alzheimers and prion diseases , another group of neurodegenerative diseases caused by protein clumping. Prion diseases are unique for one important reason: they are infectious. This new study raises the important question: could Alzheimers too be infectious?
Research About How Alzheimer’s Disease Spreads
While Alzheimer’s disease is not spread through contact with others, some research with mice seems to indicate that it could have some type of an infectious component, possibly related to prions . In prion diseases, including Creutzfeldt-Jakob disease, prion proteins begin to fold abnormally and then infect other healthy prions they encounter within the body, causing cells to die in the brain and dementia to develop. Although the unhealthy prions spread within a person, there is virtually no risk of the disease affecting other people around that individual, including family members or those caring for that person.
You May Like: Does Smelling Farts Help Prevent Dementia
A Variety Of Factors Can Trigger Neurodegenerative Disease Including Genetics Head Trauma And Neurotoxins
Despite millions of deaths, experts suggest that the prevalence of the disease will quadruple by 2050, if not sooner. Unfortunately, there is a growing stack of evidence that Alzheimers disease, Parkinsons disease and other brain diseases are transmissible. Deadly, self-replicating proteins appear to be one of the common threads. Similar proteins appear to be associated with autism and the childhood cases of Creutzfeldt-Jakob disease.
The epidemic is worse in some regions of the world than others. Finland and Iceland were at the top of the list just a few years ago. Now, countries in the Middle East and Persian Gulf states have soared to the top of the list.
In the United States, for example, deaths from Alzheimers disease increased 71 percent from 2000 to 2013. During that time, deaths from heart disease decreased 14 percent.
How Will This Benefit People With Dementia
It is becoming increasingly clear that detecting the onset of dementia early will be key to finding effective treatments. There is no known cure for any form of dementia, including CJD and other prion-related diseases. The researchers hope that by developing and refining their detection technique, they will find a way to identify when people are in the earliest stages of the disease process. This will allow the people affected to be recruited into trials or to access any treatments as soon as possible.
Once the technique has been established for prion diseases, the researchers hope to be able to further develop and test it for proteins associated with other forms of dementia such as Alzheimer’s disease.
Read Also: Will Meredith Get Alzheimer’s
New Research Suggests That Alzheimers Disease Proteins Are Prions
May 31, 2019
Alzheimers disease is the most common type of dementia, which is a class of neurological disorders, that is characterized by deteriorating memory, and can also involve difficulties thinking and even cause changes in behavior. While Alzheimers disease is not a part of the normal aging process, the risk of Alzheimers increases with age and most people that have the disease are 65 years old or older.
Recent estimates suggest that nearly 6 million people are living with Alzheimers disease in the United States, and it is the 6th leading cause of death in this country, making it a huge public health issue. There is no known cure for the disease, and most treatments are to improve the quality of life of affected individuals and their family and caregivers. There is a clear need for more research on AD to help find better treatments and eventually a cure.
Sample Collection And Processing
Patient material was obtained after the approval of local ethics committees at the University Medical Center, Goettingen. Frontal cortex samples from patients with spAD , rpAD , dementia with Lewy bodies , age-matched non-demented controls and other rapid dementias including small vessel disease , rapidly progressive dementia with Lewy bodies , and dementia with frontotemporal lobar degeneration cases were provided by the brain bank of the Institute of Neuropathology and the biobank of the Hospital Clinic-IDIBAPS, Spain, according to their biomedical study legislation . Frontal cortex samples from patients with sporadic Creutzfeldt-Jakob disease subtypes were obtained from the Department of Neurology at the University Medical Center, Göttingen, Germany. The rpAD patients met the current selection criteria for rpAD . These inclusion criteria are as follows:
Initial classification as prion diseases based on clinical features
Presence of typical AD pathological features, i.e., higher Braak stages
Post diagnostic survival time shorter than four years
Exclusion of other forms of rapid progressive dementias and copathologies e.g. prion diseases, extensive Lewy body pathology, vascular damage or tumors based on postmortem neuropathological examination
Absence of a family history suggestive of familial AD
Don’t Miss: Dementia Picking At Skin
Laboratory Bioassays Reveal A And Tau Prions In Human Postmortem Brain Samples
In the new study, the researchers combined two recently developed laboratory tests to rapidly measure prions in human tissue samples: a new Aß detection system developed in the Prusiner lab and a tau prion assay previously developed by Marc Diamond, PhD, a former UCSF faculty member who is now director of the Center for Alzheimers and Neurodegenerative Diseases at UT Southwestern Medical Center.
Unlike earlier animal models that could take months to reveal the slow spread of Aß and/or tau prions, these cell-based assays measure infectious prion levels in just three days, enabling the researchers to effectively quantify for the first time the levels of both tau and Aß prions in processed extracts from post-mortem brain samples. In the new study, they applied the technique to autopsied brain tissue from over 100 individuals who had died of Alzheimers disease and other forms of neurodegeneration, which was collected from repositories in the United States, Europe, and Australia.
Approving A Vaccine Utilizing Novel Rna Technology Without Extensive Testing Is Extremely Dangerous The Vaccine Could Be A Bioweapon And Even More Dangerous Than The Original Infection
References
Don’t Miss: Does Medicare Cover Nursing Home For Dementia