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FAQ - Form 13615

How plausible is the new model for the initiation of tau aggregation in Alzheimer's cited below?

Not very plausible at allBrief Background:Tau protein is involved in stabilizing microtubules in the brain: without tau bound, the microtubules begin to fall apart into their individual protein components. This normally is a controlled process regulated by the phosphorylation of the tau protein. For reasons poorly understood, tau clumps together to form neurofibrillar tangles that are no longer able to bind and stabilize the microtubules. Since intact microtubules are critical for axonal transport of synaptic vesicles and other neuronal processes, this causes major problems in the brain, triggering apoptosis (programmed cell death) and general neuronal dysfunction.What they found:The researchers started by isolating the tau tangles and separating all the components of the tangles by size.[1] They then tested each fraction for its ability to seed the growth of existing fibers. The expectation was that a small assembly of tau proteins would be the trigger for tangle formation; the first steps of aggregation would be difficult and rare but once the seed form aggregation would proceed rapidlyTo their surprise, they found that the most active component was a monomer, a single tau protein, that was somehow different from the other monomers. The formation of this u201cactivated monomeru201d as they called it is the supposed u201cBig Bangu201d of Alzheimeru2019s disease referred to in the article.The Big Bang is probably not what they think it is:Despite the claim in accompanying editorial,[2] the idea that the trigger for aggregation lies in the rare conformations of individual monomeric proteins is not new.[3] Back in 2024. Vladimir Uversky showed that when proteins form aggregates like tau tangles (red circles) they share a structure with a specific early protein folding intermediate, the premolten globule (cyan circles).[4] The premolten globule has secondary structure like alpha helices and beta sheets, is compact like normal proteins, but does not have the unique tertiary structure that defines a normal protein.Moving a protein closer to this partially folded state can trigger aggregation. For proteins that normally unfolded like islet amyloid polypeptide[5] and amyloid beta,[6] inducing a small amount of structure by adding a helix forming solvent like HFIP can rapidly trigger aggregation. For proteins that are normally folded like beta-microglobulin, partially unfolding the protein can have the same effect.So far so good. The problem is when they look at the characteristics of the activated monomer, specifically the energetics of the transition. Tau is an mostly unfolded protein.[7] The activated monomer that is supposed to be the seed has the nearly the exact same secondary structure - it must also be mostly unfoldedBut the authors show that not only does the activated monomer not rapidly convert back to the inactive state, it also resists heat treatment for over 24 hours before it starts to deactivate, long before most normal proteins would completely unfold. Quantitatively, the authors calculate an energy barrier of -78 kcal/mol, around 3 times as much as most other proteins[8] Since energies are on a log scale, this makes it one of the more stable proteins in existence.This is even more surprising as the activated monomer is a largely unfolded protein with little of the contacts or secondary structure that holds most proteins togetherSo what did they actually see?One obvious answer is a small contamination from a highly active higher molecular weight species. It is unlikely though that any got through the columns and filters they use in their setup. A more likely explanation is a post-translational modification. In the published reviewers comments (a neat feature of eLife) one of the reviewers points out that their tau protein elutes similar to a protein half its size. Proteolytic cleavage is known to be one of the triggers for tau aggregation.[9] My guess is that the misfolded monomer is a cleaved or otherwise modified form of the regular protein.What actually triggers tau aggregation?One surprising possible answer is a phase transition. Aggregation prone proteins often have a sharp transition point at which they undergo a liquid-liquid phase separation to form droplets of essentially liquid protein,[10][11] in this case partly controlled by the phosphorylation state of tau. Aggregates form rapidly in the droplets. But that is another answer.Related questions:What is the structure of amyloid beta before it forms a placque?How can I effectively monomerize amyloid proteins to create a reproducible starting point for research?Is amyloid formation driven by a liquid-liquid phase transition?Footnotes[1] Inert and seed-competent tau monomers suggest structural origins of aggregation[2] Alzheimeru2019s Disease: The two shapes of the Tau protein[3] Mechanisms of amyloid formation revealed by solution NMR[4] Conformational constraints for amyloid fibrillation: the importance of being unfolded.[5] Direct detection of transient?-helical states in islet amyloid polypeptide[6] A partially folded structure of amyloid-beta(1-40) in an aqueous environment.[7] The natively unfolded character of tau and its aggregation to Alzheimer-like paired helical filaments.[8] http://www.msg.ucsf.edu/agard/Pu...[9] Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease[10] Probing the Sources of the Apparent Irreproducibility of Amyloid Formation: Drastic Changes in Kinetics and a Switch in Mechanism Due to Micellelike Oligomer Formation at Critical Concentrations of IAPP[11] Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau.

What is Alzheimer's disease and how does it affect the body?

A viable pathological hypothesis for the development of Alzheimer's disease is as follows:Alzheimer's disease results from the slow build up over a lifetime of atherosclerosis in the intracranial arteries of the cortex. The build up of atherosclerosis compromises a process that piggybacks on the pulsating elastic expansion and contraction of healthy arteries for the pumping of cerebrospinal fluid (CSF) through aquaporins that form a spiraling sheath over the outside walls of the arteries. That pumping action which circulates CSF throughout the area of the brain served be each artery gradually becomes reduced as the walls of the arteries lose their elasticity and harden. Finely, a sufficiently reduced pumped volume of circulating CSF creates a statistical probability that during recovery from activation, a negatively charged neuron in the cortex will occasionally undergo a seizure by capturing a nearby K+ ion and be destroyed, thus leading into the development of Alzheimer's symptoms due to the destruction of neurons. (The adequate circulation of CSF in a healthy brain washes away K+ ions and thus maintains a virtually negligible probability for their capture by negatively charged neurons during recovery from activation.)Alzheimer's brains shrink in size because the development of atherosclerosis significantly restricts the flow of blood through the arteries and starves the neurons of nourishment. The tau tangles that form in Alzheimer's brains are the remnants of destroyed neuronsThe following reference which can be viewed on the Internet illustrates the molecular biological process for neuron destruction due to a compromised circulation of CSF and a resulting inadequate clearance of K+ ions:u201cDelayed K+ clearance associated with aquaporin-4 mislocation: Phenotypic defects in brains of?-syntrophin-null mice.u201d Proceedings of the National Academy of Sciences Volume 100 No. 23 Pages 13615-13620 - Amiry-Moghaddam et al

What theories are there for the greatly increased rates of dementia?

The top reason or u201ctheoryu201d to explain an increase in the number of cases of dementia is an u201caging societyu201d u2024 at least in the West. That is, life expectancy has increased, and birth rates have decreased. Therefore, with more of the population in advanced age than ever before, we have higher u201cratesu201d of age-related diseases and conditions that cause dementia. However, when you look at age-related prevalence, it does not seem that is increasing u2024 it is simply due to societyu2019s overall advanced age. While it might appear to be more common, advances in diagnosing dementia and itu2019s causes has lead to earlier recognition. So a second explanation is in medical advances in diagnosis; a third theory might be that today, there is less stigma with dementia so people are more free to share their diagnosis - or the diagnosis of loved ones.

What does the top 20 percentile mean on JEE mains normalisation?

Most of the JEE Main aspirants must be aware of the fact that JEE Main Rank List is prepared after finding a composite score of JEE Main scores and Normalized Marks of Class XII in the ratio of 60:40. But very few know what actually is this normalization procedure and how nromalised score for class 12 results are calculated. JEE Main Merit Ranks form the basis of the admissions to undergraduate engineering courses at prestigious 31 NITs, 18 IIITs, 18 GFTIs and many other engineering institutions across India.Let's first understand a few concepts first.Percentage of marks and Percentile are though related but completely differentThe Percentage of marks and Percentile are totally different entities. Percentage is your marks out of a total of 100, whereas percentile score of a candidate reflects percentage of candidates scoring below a particular candidate in that exam.Calculation of percentile of a candidate:The percentile score of a candidate shows the score of the candidate with respect to the number of students.Thus we calculate the percentile score as below:Number of candidates in the group with aggregate marks less than the candidate x 100Total number of the candidates in the groupLetu2019s understand it more clearly with the help of few examples-Suppose in a particular board, the total number of candidates registered is 13918 and number of candidates appeared is 13711, the percentile of the candidate will be calculated in the following way-Example 1: Where a student has scored 50% in the exam and there are 2218 candidates, who have scored less than the candidates, i.e., less than 50%:2218u00a0 x 100 = 16.1813711Here, the percentile score of the candidate from exam is 16.18 while his/her percentage in the exam is 50%.Example 2: Where a student has scored 60% in the exam and there are 6865 candidates, who have scored less than the candidates, i.e. less than 60%:6865 x 100 = 50.0713711Here, the percentile score of the candidate is 50.07 while his/her percentage is 60%.Example 3: Where a student has scored 90% in the exam and there are 13615 candidates, who have scored less than the candidates, i.e. less than 90%:13615 x 100 = 99.313711Here, the percentile score of the candidate from the exam is 99.3 while his/her percentage is 90%.Subjects considered for Percentile Score:Five subjects will be taken into account for calculation of percentile and normalization of qualifying examination marks for paper 1 (B.E./B. Tech.) and paper 2 (B. Arch./B. Planning) of JEE Main.These subjects are:Language,Physics,Mathematics,Any one of (Chemistry, Biology, Biotechnology, Technical Vocational Subject),Any other subjectNote : In case a candidate has appeared in six subjects in the qualifying examination, the subject (fifth or sixth) with better marks will be considered.Candidates, who appear for improvement, will have to appear for all the subjects and not one or two which they wish to improve in.Important: Candidates, who are appearing in the improvement examination to improve their qualifying examination marks, will get only one chance to inform JEE (Main) Unit as to which year qualifying examination marks have to be considered for the purpose of declaration of final merit of JEE Main.Considerations for JEE Main & JEE Advanced:The percentile score a candidate gets in the board will mainly contribute to normalized marks to be used for the Merit Ranks of JEE Main and for qualifying for JEE Advanced.Candidates may note that the normalized qualifying examination marks will be based on the position of the candidate in his/her respective board (i.e. the above mentioned percentile score).It is important to note here that the weightage of normalized qualifying examination marks is only for deciding ranking of JEE Main for admissions to all Centrally Funded Technical Institutions (CFTIs)/ NITs/IIITs but not for IITs.Factors used in calculation of normalized qualifying examination marks:JEE Main Marks of all canddiates from the same board whose subject combinations meet the eligibility criteria of JEE MainJEE Main Marks of all candidates (on All India Basis) whose subject combinations meet the eligibility criteria of JEE Main students in JEE MainProcedure for Normalization of Class XII marks for JEE Main Rank Calculation:For your easy understanding, we bring you step-by-step process to calculate your normalised score of class XII marks.Normalised score of your class XII marks is actually the average of two JEE Main scores. what are these two JEE Main scores? The two JEE Main scores are derived by directly linking your Class XII Results to overall JEE Main Results.Here is how?Step 1: On the basis of your Class XII results, your percentile is calculated. You can calculate your percentile by using the formula below-Number of candidates in your board with aggregate marks less than you*100Total number of candidates in the groupu00a0Example:Let's assume that your score is 60 percent from a particular board where a total of 13,711 candidates are eligible for JEE Main. Also suppose number of canddiates scoring less than 60 per cent marks in your board is 6,865. Now, on basis of your ranking in the board result your percentile will be calculated as below:Number of candidates in your board with aggregate marks less than you*100Total number of candidates in the group= 6865*100 = 50.07 percentile13711Step 2: Scores of all JEE Main canddiates appearing on All India basis are arranged in Merit and their percentile is derived. Here, we assume that the total number of JEE Main eligible candidates on All India basis is 11,53,667. The JEE Main score belonging to the corresponding JEE Main percentile of your Class XII percentile (P) is figured now. Let it be B1Example:As shown in the image below, let's assume that JEE Main marks for a JEE Main percentile which is equal to your board percentile is 48. Thus B1=48.Step 3: Now, scores of all JEE Main eligible canddiates appearing from your Class XII Board are arranged in Merit and again their percetile is derived. Again, the JEE Main score belonging to the corresponding JEE Main percentile of your Class XII percentile (P) is figured. Let it be B2.Example, as shown in the image below, let's assume that JEE Main marks for a JEE Main percentile which is equal to your board percentile is 80. Thus B2=80.Step 4: Now average of B1 and B2 is your actual normalised score. Thus your normalised score isB1+B2 = 48+80 = 642 2Now, assuming that your JEE Main score is 90, the composite score calculated for your JEE Main Rank list will be:(JEE Main Marks)*60+ (Normalised score of Class XII marks)*40100= (90*60)+(64*40) = 5400+2560 = 7960 = 79.60100 100 100Finally, this composite score is arranged in merit order and the rank are derived accordingly.Thus, from the formulae and the process above, you can understand how JEE Main Normalized Score and Class XII Percentile are calculated to derive JEE Main Rank.

What are some good books on Alzheimer's (nonfiction or fiction)?

Many of my choices are specific to Frontal Temporal Dementia, which a good friend is battling. Some are about Dementia in general and some are specific to Alzheimeru2019s but can be applied to all the Dementiau2019s.Among the Alzheimeru2019s books I donu2019t think you can top The Mayo Clinic on Alzheimeru2019s Disease. Another is The 36 Hour Day by Mace and Rabins. It is particularly helpful for caregivers. Another good one for caregivers is What If Itu2019s Not Alzheimeru2019s? by Lisa Radin and Gary Radin.Also in the field of caregivers are a few that are more about Frontal Temporal Dementia but believe me, the ladies know their stuff. There is Dementia: The Journey Ahead by Susan Scarff and The Dance by Deborah G. Thelwell.Dementia A Clinical Approach by JMS Pearce gives a good overview. But my all time top book is Dementia A Clinical Approach by Cummings and Benson.If you are a little tight on money or just want a good overview send off for the free publications from the US Government: Alzheimer's Disease and Related Dementias or 1u2013800u2013438u20134380.

How does Alzheimer's destroy the brain cells?

The first thing to happen is the destruction of the connections between neurons, resulting in forgetfulness. After that, beta amyloid plaques and neurofibrillary tangles rob the still healthy neurons of nutrients and the ability to self repair small damages. Hereu2019s a good discussion of the kinds of brain structures involved and how Alzheimeru2019s affects them.What Happens to the Brain in Alzheimer's Disease?.

What does the research say about football participation and CTE?

Published studies as identified below in italics are correlated to provide the following explanation for the development of CTE. (The identified studies can be viewed on the Internet.)As indicated in the following study an inadequate circulation of cerebrospinal fluid (CSF) for clearance of toxic K+ ions leads to the potential destruction of neurons during their recovery from activation.u201cDelayed K+ clearance associated with aquaporin-4 mislocation: Phenotypic defects in brains of?-syntrophin-null mice.u201d Proceedings of the National Academy of Sciences Vol.100 No. 23 13615-13620Other published information, typically as included in the following identified study, reveals that tau tangles (which are the remnants of destroyed neurons) form in clusters that surround small blood vessels (e.g. arteries) in the cortex of CTE brains.u201cThe neuropathology of chronic traumatic encephalopathyu201d Brain Pathology, May 2015The following pathogenesis for CTE follows from information in such studies.Pressurized by blood, arteries in the brain form a rigid structural network within the soft fatty material of the brain. An impact on the head indents the soft brain material into the rigid network of arteries and repeated impacts enlarge that indenting and tend to add permanence for the indenting damage.The indents which form in the soft brain material tend to distort or crush nearby passages in the brain for the circulation of CSF and thus disrupt the cleansing flow of CSF needed to effectively wash away K+ ions which are emitted from the neurons at the time they become activated. Following its emission of a K+ ion an activated neuron is left with a negative internal electrical charge and during recovery from activation there is a period of time while the neuron still retains its negative electrical charge which puts it in jeopardy of capturing any nearby K+ ion that has not been washed far enough away by a healthy flow of CSF. Upon such capture of a K+ ion the neuron will undergo an excitotoxic seizure which destroys the neuron and thus completes a process that explains how CTE develops from the destruction of neurons when the flow of CFS is compromised by damage in areas surrounding the arteries in the cortex of the brain.

What is chronic traumatic encephalopathy?

Autopsied CTE brains show that neuron destruction is greatest within a radius in close proximity to the arteries and decreases with distance from the arteries. this suggests the following tentative hypothesis for the pathology of CTE.Arteries in the brain are inflated by blood pressure which turns them into rigid structures within the soft fatty texture of the brain and an impact to the head would the compress and indent the soft fatty texture of the brain into the rigid structure of the arteries. Repeated impacts to the head would tend to deepen the indentations and contribute to their permanence. Such an indentation would tend to crush passages in the brain for the circulation of cerebrospinal fluid (CSF) and thus compromise its circulation in the proximity of the indentation. The extent of such damage and resulting disruption in the flow of CSF would decrease with distance from the artery.Each time a neuron is activated it emits a K+ ion which creates a negative internal electrical charge within the neuron.. An absolutely vital purpose of the CSF circulating in the brain is to rapidly wash away such K+ ions because a neuron in the stage of recovery from activation where it still retains that negative charge must not come into close proximity to any K+ ion and capture it. Such capture of a K+ ion during recovery from activation causes a neuron to undergo a seizure which destroys it.The circulation of CSF in an undamaged brain washes away K+ ions so effectively that there is only an infinitesimal probability for capture of K+ ions, but the statistical probability for capture of a K+ ion increases exponentially in areas of the brain where the circulation of CSF becomes compromised and the resulting destruction of neurons is the cause of CTE.A reference which confirms the destruction of neurons by a compromised circulation of CSF is: u201cDelayed K+clearance associated with aquaporin-4 mislocation: Phenotypic defects in brains of?-syntrophin-null mice.u201d Proceedings of the National Academy of Sciences Vol.100 No. 23 13615-13620 Amiry-Moghaddam et alTau tangles that form near the arteries in CTE brains are the remnants of destroyed neurons.

What is the single most important discovery made in the study of Alzheimer's disease which has had the biggest impact on reducing symptoms of the disease and how?

Let me be clear. We do not know what causes Alzheimer's and we currently have no truly effective treatment for it. There have been, thus far, no u2018eureka momentsu2019. Yes, we do have a few medications which are capable of slowing down the rate of disease progression, but that's it and it ain't much. Nothing you read online or in lay print media regarding the prevention of Alzheimer's Dementia has any substantial merit, at least from the scientific perspective. Probably the best hope we have right now is the discovery that the body's immune response to certain common viruses (Herpes Zoster, which causes shingles, for example) may be intimately involved with Alzheimer's. Factors modulating this immune response range from genetic predisposition to environmental triggers. The situation remains complex and is still hypothetical, but the science supporting these concepts is quite groundbreaking, so much so that the large scale study has been referred to as a u2018landmarku2019. Where all this will lead is only a matter of speculation right now, but there is little doubt that a specific avenue for research is now open for traffic.Edit:John Dorey submitted the following hypothesis concerning the pathogenesis of Alzheimers Disease culled from the National Academy of Sciences:Alzheimeru2019s HypothesisIn a catechol-o-methyl transferase reaction norepinephrine released in the cortex of the brain breaks down elastic polymers and homocysteine-cysteine u201cbridgesu201d in the outside walls of the arteries while both norepinephrine and epinephrine in the blood stream do the same damage to the inside walls, resulting in a gradual build-up of atherosclerosis in those arteries. The extent of atherosclerosis that has built up over many years significantly restricts the flow of blood through the arteries causing Alzheimer's brains to shrink from a lack of nourishment in support of neuron activity and the beta amyloid deposits that form in Alzheimer's brains are the misfolded protein remnants of broken down polymers from the outside walls of the damaged arteries. Mental, physical and chemical types of stress and a metabolic magnesium deficiency all tend to promote the release of norepinephrine and epinephrine thus accelerating the build up of atherosclerosis for an increased risk of developing Alzheimer's disease during a person's lifetime.Cerebrospinal fluid (CSF) is pumped through aquaporins wound in a covering spiral over the arteries in the brain and the pulsating elastic expansion and contraction of healthy arteries pressing against the covering of aquaporins provides the pumping mechanism for the flow of CSF through the aquaporins and its circulation throughout the individual areas of the brain served by each artery. As atherosclerosis builds up in the arteries their walls harden and cause the pumping action for circulation of CSF to become reduced due to a loss of pulsating arterial expansion and contraction. The build-up of beta amyloid deposits in the brain also tends to obstruct the circulation of CSF; therefore, the circulation of CSF becomes compromised both by the build-up of beta amyloid deposits and by a steadily decreasing pumped volume of CSF through the aquaporins. (A reduced circulation of CSF due to developing atherosclerosis may be a precursor to the build up of beta amyloid deposits in the brain because a healthy circulation of CSF could tend to wash away beta amyloid material as it is being produced.)At the start of each activity cycle, neurons in the brain emit a K+ ion and thus acquire an internal negative electrical charge. During recovery from activation a neuron which still retains its negative internal electrical charge before achieving electrical equilibrium will undergo an excitotoxic seizure and be destroyed if it happens to capture a nearby K+ ion which has not been washed far enough away by the circulation of CSF. The circulation of CSF in healthy brains establishes a virtually negligible probability for the capture of K+ ions but the statistical probability for capture of K+ ions during recovery from activation increases exponentially in areas of the brain where the circulation of CSF becomes compromised. A compromised inadequate circulation of cerebrospinal fluid and the resulting destruction of neurons is the direct cause of Alzheimer's disease. A reference which confirms the destruction of neurons by a compromised circulation of CSF is:u201cDelayed K+clearance associated with aquaporin-4 mislocation: Phenotypic defects in brains of?-syntrophin-null mice.u201dProceedings of the National Academy of Sciences Vol.100 No. 23 13615-13620 PMID: 14597704Amiry-Moghaddam et alThe tau tangles that form in Alzheimer's brains are the remnants of destroyed neurons.This hypothesis is notable for its detail and testable predictions. It summarizes a mechanism by which compromised circulation of cerebrospinal fluid results in destruction of neurons and the consequential laying down of tau proteins, the initial trigger for all of this being atherosclerosis of the cerebral vasculature. This hypothesis leaves considerable room for genetically induced modulation of the entire process, along with a number of possible environmental modifiers. It is a good example of how scientific dialogue should be conducted and suggests another attractive path for ongoing research. Thanks, John.

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13615 Form: What You Should Know

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