Brain, emotion, sight and sound processing, concussion and Parkinson

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DID HANS ASPERGER ACTIVELY ASSIST THE NAZI EUTHANASIA PROGRAM?

Researchers have investigated Hans Asperger’s Nazi era publications and have revealed he actively cooperated with the Nazi’s euthanasia program. The Kinder-Euthanasie (child euthanasia) program resulted in the murder of thousands of physically and mentally disabled children under Nazi rule. READ MORE…

Brain injury, concussive force of military blasts and Alzheimer’s – tau protein

Tau proteins (or τ proteins, after the Greek letter with that name) are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.[5] Pathologies and dementias of the nervous system such as Alzheimer’s disease and Parkinson’s disease [6] are associated with tau proteins that have become defective and no longer stabilize microtubules properly.

The tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT(microtubule-associated protein tau) and is located on chromosome 17.[7][8]

The tau proteins were identified in 1975 as heat stable proteins essential for microtubule assembly [9][10] and since then, they have been characterized as intrinsically disordered proteins.[11]

Neurons were grown in tissue culture and stained with antibody to MAP2 protein in green and MAP tau in red using the immunofluorescence technique. MAP2 is found only in dendrites and perikarya, while tau is found not only in the dendrites and perikarya but also in axons. As a result, axons appear red while the dendrites and perikarya appear yellow, due to superimposition of the red and green signals. DNA is shown in blue using the DAPI stain which highlights the nuclei.

Function

Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are found mostly in neurons compared to non-neuronal cells. One of tau’s main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knockout mice that did not show abnormalities in brain development – possibly because of compensation in tau deficiency by other MAPs.[12] Tau is not present in dendrites and is active primarily in the distal portions of axons where it provides microtubule stabilization but also flexibility as needed. This contrasts with MAP6 (STOP) proteins in the proximal portions of axons, which, in essence, lock down the microtubules and MAP2 that stabilizes microtubules in dendrites.

Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules.[10]Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.

Structure

Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in exons 2, 3, and 10 of the tau gene.

Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.[13]

Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.[14]

Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[15] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.[16] Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, PP2A and PP2B are both present in human brain tissue and have the ability to dephosphorylate Ser396.[17] The binding of these phosphatases to tau affects tau’s association with MTs.

Genetics

In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons.[citation needed] The major tau protein in the human brain is encoded by 11 exons.[citation needed] Exons 2, 3 and 10 are alternatively spliced, allowing six combinations (2310; 2+310; 2+3+10; 2310+; 2+310+; 2+3+10+). Thus, in the human brain, the tau proteins constitute a family of six isoforms with the range from 352-441 amino acids. They differ in either zero, one, or two inserts of 29 amino acids at the N-terminal part (exon 2 and 3), and three or four repeat-regions at the C-terminal part (exon 10). So, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total).

The MAPT gene has two haplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer’s disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copy of the gene, resulting in congenital defects.[18][19][20][21]

Clinical significance

Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer’s diseasefrontotemporal dementia, and other tauopathies.[22]

All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from Alzheimer’s disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.

Recent research suggests that tau may be released extracellularly by an exosome-based mechanism in Alzheimer’s disease.[23][24]

Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies.[25]

Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.[26]

Traumatic brain injury

Repetitive mild traumatic brain injury (TBI) is now recognized as a central component of brain injury in contact sports, especially American football,[27][28] and the concussive force of military blasts.[29] It can lead to chronic traumatic encephalopathy (CTE) that is characterized by fibrillar tangles of hyperphosphorylated tau.[30]

High levels of tau protein in fluid bathing the brain are linked to poor recovery after head trauma.[31]

Tau hypothesis of Alzheimer’s disease

The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs (neurofibrillary tangles). Tau protein is a highly soluble microtubule-associated protein (MAP).[10] Through its isoforms and phosphorylation tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from AD.

Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans.[6] Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAP 1(microtubule associated protein1), MAP 2, and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.

Meet the syndicate: Assassin, accomplices, stooges

Even though p-tau showed the strongest correlation with cognitive decline, and amyloid-beta only a slight correlation, that doesn’t mean that p-tau is committing the crime inside cells all by itself while amyloid loiters in spaces outside of cells in large gangs, creating a distraction. Mitchell’s data analysis has pointed to dynamics more enmeshed than that.

“Though the study had clear trends, it also had a good bit of variance that would indicate multiple factors influencing outcomes,” Mitchell said. And a particular manifestation of amyloid-beta has piqued the researchers’ ire.

Little pieces are water soluble, that is, not tied up in clumps of plaque. The data has shown that these tiny amyloids may be up to no good. After p-tau levels, the study revealed that those of soluble amyloid-beta had the second-strongest correlation with cognitive decline.

“Lumpy amyloid-beta, the stuff we see, ironically doesn’t correlate as well as with cognitive decline the soluble amyloid,” Mitchell said. “The amyloid you don’t see is like the sugar in your tea that dissolves and hits your taste buds versus the insoluble amyloid, which is more like the sugar that doesn’t dissolve and stays at the bottom of the cup.”

Some Alzheimer’s researchers have cited evidence indicating that free-floating amyloid helps produce the corrupted p-tau via a chain of reactions that centers around GSK3 (Glycogen synthase kinase 3), an enzyme that arms tau with phosphorous, turning it into a potential biochemical assassin.

Incidentally, Mitchell’s study also looked at un-phosphorylated tau and found its levels do not correlate with cognitive decline. “That makes sense,” Mitchell said. “Regular tau is the backbone of our neurons, so it has to be there.”

Also, p-tau is a normal part of healthy cells, but in Alzheimer’s it is wildly overproduced.

Massive dataset: 528 mice rat out p-tau

One advantage of data mining 51 existing studies versus doing one new lab experiment, is that the cumulative analysis adds the sample sizes of so many studies together for a whopping grand total. Mitchell’s analysis encompassed results from past experiments carried out on, all totaled, 528 Alzheimer’s mice.

A previous study Mitchell led had already indicated that amyloid-beta plaque levels may not be the most productive target for drug development. Separate reports by other researchers on failed human trials of drugs that fought plaque would seem to corroborate this.

neurons

Mitchell’s prior analysis examined lab studies that used an Alzheimer’s lab mouse model that did not allow for the study of p-tau. Mitchell’s current analysis covered studies involving a different mouse model that did allow for the observation of p-tau.

Mitchell’s latest findings have corroborated the prior study’s findings on amyloid, and also added p-tau as a key suspect in cognitive decline.

Principal investigator: My take on possible treatments

To arrive at the 51 studies with data suitable for inclusion in their analysis, Mitchell’s research team sifted through hundreds of Alzheimer’s research papers, and over time, Mitchell has examined a few thousand herself. She has gained some impressions of how biomedical research may need to tackle the disease’s slippery biochemical labyrinth.

“When we see multifactorial diseases, we tend to think we’ll need multifactorial treatments,” Mitchell said. “That seems to be working well with cancer, where they combine chemotherapy with things like immunotherapy.”

Also, Alzheimer’s diagnosticians might be wise to their adopt cancer colleagues’ early detection stance, she said, as Alzheimer’s disease appears to start long before amyloid-beta plaque appears and cognitive decline sets in.

Above all, basic research should cast a broader net.

“I think p-tau is going to have to be a big part,” she said. “And it may be time to not latch onto amyloid-beta plaque so much like the field has for a few decades.”

Data Detectives Shift Suspicions in Alzheimer’s from Usual Suspect to Inside Villain

Concussion Leaves The Brain Vulnerable To PTSD

There’s growing evidence that a physical injury to the brain can make people susceptible to post-traumatic stress disorder.

Studies of troops who deployed to Iraq and Afghanistan have found that service members who have suffered a concussion or mild traumatic brain injury are far more likely to develop PTSD, a condition that can cause flashbacks, nightmares and severe anxiety for years after a traumatic event.

And research on both people and animals suggests the reason is that a brain injury can disrupt circuits that normally dampen the response to a frightening event. The result is like “driving a car and the brake’s not fully functioning,” says Mingxiong Huang, a biomedical physicist at the University of California, San Diego.

Scientists have suspected a link between traumatic brain injury (TBI) and PTSD for many years. But the evidence was murky until researchers began studying troops returning from Iraq and Afghanistan.

What they found was a lot of service members like Charles Mayer, an Army sniper from San Diego who developed PTSD after finishing a deployment in Iraq.

In 2010, Mayer was on patrol in an Army Humvee near Baghdad when a roadside bomb went off. “I was unconscious for several minutes,” he says. So he found out what happened from the people who dragged him out.

The blast fractured Mayer’s spine. It also affected his memory and thinking. That became painfully clear when Mayer got out of the Army in 2012.

“Two weeks later, I started school,” he says. “And a simple math equation like 120 times 7, where I previously would do that in my head very easily, I all of a sudden couldn’t do that.”

And Mayer had a bigger problem. His time in Iraq had left him with an uncontrollable fear of improvised explosive devices, or IEDs.

“When I would walk down the street, I would walk away from trash piles because that’s often how they would hide IEDs,” he says. “I stayed away from large crowds.”

Mayer’s fear was not only disturbing, it was disabling. “I would get severe panic attacks to the point where I would have to go to the hospital,” he says. “I would feel like I’m actually having a heart attack.”

Eventually, Mayer went to a Veterans Affairs hospital for help. An exam confirmed that he had PTSD.

The wars in Iraq and Afghanistan have produced thousands of Charles Mayers. First they got a concussion from a bomb blast. Then they got PTSD.

“We had people who were looking very miserable when they came back,” says Dewleen Baker, a psychiatrist at UCSD and the VA San Diego Healthcare System.

Baker kept asking herself: Was the PTSD just from the emotional trauma of combat? Or did a concussion alter the brain in a way that amplified fear and anxiety?

“I could easily diagnose the PTSD,” she says. “But I found it very, very difficult to tease apart the contribution of traumatic brain injury.”

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Mayer in Iraq in 2010, where he served as a sniper and was injured in a roadside explosion.

Courtesy of Charles Mayer

So Baker and a team of researchers began studying more than 1,600 Marine and Navy service members from Camp Pendleton, in San Diego County, Calif. The service members had been assessed before deploying to Iraq or Afghanistan, and then again three months after returning.

“At one point we got this battalion that went to Helmand province in Afghanistan, and literally 50 percent of them were complaining of blast exposures and symptoms,” Baker says. “I got concerned.”

Baker had reason to worry. The study found that troops who experienced a traumatic brain injury were twice as likely to develop post-traumatic stress disorder.

But why? There was no easy way to answer that question in people. But several years ago some answers began to emerge from animal studies.

In one experiment, a team of scientists at the University of California, Los Angeles compared healthy rats with rats that had experienced a traumatic brain injury. All of the rats received a type of behavioral conditioning known to induce fear.

They found that fear response learned by the animals that had experienced a TBI was much greater than it normally would be, says Michael Fanselow, a psychology professor at UCLA and an author of the study.

Next, the team looked at cells in the amygdala, a part of the brain that takes sensory information and decides whether to be afraid. They found changes that would amplify the animal’s response to a frightening experience.

“And we think that that’s the way TBI has of increasing your susceptibility to post-traumatic stress,” Fanselow says.

If brain injuries really do change the brain’s fear circuitry, there should be some way to detect that change in people, says Baker.

So Baker teamed up with her colleague Mingxiong Huang, the biomedical physicist. Huang has been using a technology that measures electrical activity in the brain. It’s called magnetoencephalography,or MEG.

Huang and a team of researchers used MEG to scan the brains of 84 people who had experienced a brain injury. Some of the participants were service members, some were civilians.

Those scans found abnormal signals coming from the brains of people who’d had a concussion. And the location of those abnormal signals suggested that there was too much activity going on in the amygdala and not enough in an area that normally tempers emotional reactions.

The result is a brain that is “like a car with no brake,” Huang says.

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After leaving the Army and starting school, Charles discovered he could no longer do simple math equations in his head.

Stuart Palley for NPR

To learn more about the brain circuitry involved in both TBI and PTSD, Dewleen Baker is expanding her earlier study of Marines. She plans to scan the brains of about 200 combat veterans, including some with both TBI and PTSD.

And Baker will have help from a researcher with a personal stake in the project: Charles Mayer, the former soldier whose college career was interrupted by PTSD.

After getting treatment, Mayer was able to finish his undergraduate degree in December. Then Mayer, who is now 30, started looking for a job that would let him study the problems that had affected his own brain.

“I looked up the psychiatrists that were doing research that I really cared about, and Dr. Baker was definitely up there,” he says. And Baker hired him.

Their research will focus on veterans. But the findings could also help identify civilians who’ve suffered a brain injury that could make them vulnerable to PTSD.

http://www.npr.org/sections/health-shots/2016/09/26/495074707/war-studies-suggest-a-concussion-leaves-the-brain-vulnerable-to-ptsd

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