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First of its kind study may lead to new era of Alzheimer's drug discovery and therapeutic targets
July 24, 2017
Arizona State University
Neuroscientists have identified a new way for brain cells to become fated to die during Alzheimer's diseases. The research team has found the first evidence that the activation of a biological pathway called necroptosis, which causes neuronal loss, is closely linked with Alzheimer's severity, cognitive decline and extreme loss of tissue and brain weight that are all advanced hallmarks of the disease.
Alzheimer's disease tragically ravages the brains, memories and ultimately, personalities of its victims. Now affecting 5 million Americans, Alzheimer's disease is the sixth leading cause of death in the U.S., and a cure for Alzheimer's remains elusive, as the exact biological events that trigger it are still unknown.
In a new study published today, Arizona State University-Banner Health neuroscientist Salvatore Oddo and his colleagues from Phoenix's Translational Genomics Research Institute (TGen) -- as well as the University of California, Irvine, and Mount Sinai in New York -- have identified a new way for brain cells to become fated to die during Alzheimer's diseases.
The research team has found the first evidence that the activation of a biological pathway called necroptosis, which causes neuronal loss, is closely linked with Alzheimer's severity, cognitive decline and extreme loss of tissue and brain weight that are all advanced hallmarks of the disease.
"We anticipate that our findings will spur a new area of Alzheimer's disease research focused on further detailing the role of necroptosis and developing new therapeutic strategies aimed at blocking it," said Oddo, the lead author of this study, and scientist at the ASU-Banner Neurodegenerative Disease Research Center at the Biodesign Institute and associate professor in the School of Life Sciences.
The findings appear in the advanced online edition of Nature Neuroscience.
Necroptosis, which causes cells to burst from the inside out and die, is triggered by a triad of proteins. It has been shown to play a central role in multiple sclerosis and Lou Gehrig' disease (amyotrophic lateral sclerosis, or ALS), and now for the first time, also in Alzheimer's disease.
"There is no doubt that the brains of people with Alzheimer's disease have fewer neurons," said Oddo. "The brain is much smaller and weighs less; it shrinks because neurons are dying. That has been known for 100 years, but until now, the mechanism wasn't understood."
Links with Alzheimer's
Necroptosis was first identified as a result of inflammation, a common malady in Alzheimer's.
Three critical proteins are involved in the initiation of necroptosis, known as RIPK1, RIPK3 and MLKL. The study describes a key event in the process of necroptosis when RIPK1 and RIPK3 form a filamentous structure known as the necrosome.
The formation of the necrosome appears to jump-start the process of necroptosis. It activates MLKL, which affects the cell's mitochondria, eventually leading to cell death.
Winnie Liang, TGen assistant professor, director of TGen Scientific Operations and director of TGen's Collaborative Sequencing Center, said MLKL executes necroptosis to ultimately cause cell death.
"In this study, we show for the first time that necroptosis is activated in Alzheimer's disease, providing a plausible mechanism underlying neuronal loss in this disorder," said Liang, who contributed to the study's gene expression analyses.
To explore necroptosis, the research team utilized multiple cohorts of human samples obtained from the Brain and Body Donation Program at the Banner Sun Health Research Institute and Mount Sinai VA Medical Center Brain Bank.
First, they measured RIPK1, RIPK3 and MLKL in a specific region of the brain that is typically ravaged by cell loss during the advance of Alzheimer's disease -- the temporal gyrus. Results showed that during necroptosis, these markers were increased in the brains of people with Alzheimer's disease.
Next, they identified the molecular cascade of necroptosis activation, with RIPK1 activating RIPK3 by binding with it. This protein complex then binds to and activates MLKL. Analysis of mRNA and protein revealed elevated levels of both RIPK1 and MLKL in the postmortem brain tissues of patients with Alzheimer's when compared with normal postmortem brains.
Furthermore, they also demonstrated that necroptosis activation correlated with the protein tau. Intriguingly, necroptosis did not appear to be linked with the other chief physiological characteristic of Alzheimer's pathology, beta-amyloid plaque.
Engines of decline
To assess the relationship between necroptotic protein levels and cognitive health, the study revisited the scores of patients whose postmortem brain tissue was evaluated for necroptosis. Results showed a significant association between RIPK1, MLKL and diminished scores on the Mini-Mental State Examination (MMSE), a widely used test measuring cognitive health.
Given the established relationship between necroptosis and Alzheimer's pathology, including cell loss and attendant cognitive deficit, the study sought to inhibit the process to study the dynamic effects on cell death and memory loss.
With such experiments not possible in people, the team demonstrated in a mouse model of the disease that lowering the activation of the necroptosis pathway reduces cell loss and improves performance in memory-related tasks, offering new hope for human therapeutics to halt or reverse the effects of Alzheimer's.
The results reveal that the inhibition of necroptosis activation through the blockage of RIPK1 prevents cell loss in mice. Compellingly, mice with inhibited activation of necroptosis pathways performed significantly better in tests of spatial memory involving navigation through a water maze.
New understanding, new hope
The study opens a new window on Alzheimer's research and offers hope for therapies targeting cell loss in the brain, an inevitable and devastating outcome of Alzheimer's progression.
Oddo stresses that RIPK1, RIPK3 and MLKL are among many potential drug targets, and others will likely follow as the links between necroptosis and Alzheimer's become clearer. While multiple causes of the disease are likely, understanding more clearly all targets that trigger disease will offer the best hope since neuronal loss has been found in people more than a decade before any symptoms of dementia.
"One may not agree as to which molecules trigger Alzheimer's disease, " said Oddo, "but everybody agrees that the end result is the neuronal loss. If you can prevent that you may have a beneficial effect."
Men risk their lives in wars so women can enjoy societies where they can pursue feminist goals, such as punishing men for sexist language.
People suffering with the metabolic condition regularly produce a range of strong bodily odours including rotten fish, onion and faeces – Kelly describes her own smell as ‘fishy-oniony.’
Her smell was so potent that at one point Kelly, from Oldham, Greater Manchester, was having four showers a day – scrubbing her skin until it was red raw to rid herself of the odour.
After receiving several complaints about her smell at work over the years, the 36-year-old suffers with severe anxiety and works night shifts at her job as a radiographer to limit the amount of people she is exposed to.
At one stage, Kelly was having four showers a day, changing her uniform twice and using whole cans of deodorant to try and mask the smell – none of which worked.
Kelly said: “Besides the smell itself, there are very few other symptoms at all and of course you have the side effects of anxiety, social isolation – it’s hard.
“As far as I know, this condition affects 300 to 600 people worldwide – it’s not very well known.”
Kelly’s condition means her body is unable to break down certain compounds found in foods that contain a substance called choline.
This results in the body disposing these compounds in a person’s sweat, breath and urine instead – emitting the most pungent of smells that Kelly herself cannot detect.
She said: “Having no sense of smell, I don’t know with me what really affects it.
“There is no magic pill that you can take to make it better, I personally take a cocktail of medications.
“One of the things they [the doctors] turn around and say to you is: ‘If it smells going in, it’s going to smell going out.’
“So things like fish and seafood are major triggers.”
Kelly’s lack of smell is an unfortunate coincidence and is not part of the condition.
Despite only receiving a diagnosis two years ago, Kelly doesn’t know whether it was passed to her genetically or she developed it during her later youth.
But she began to notice something was wrong during her early school years.
Kelly said: “There was more than one occasion where I would say: ‘I’ve had fish paste sandwiches for my lunch,’ when kids would say ‘You smell like fish.’
“That was difficult to deal with as a teenager.
“I was spending a stupid amount of time in the shower just before my diagnosis. Using red hot water, scrubbing until my skin was bright red and it was just too stressful.”
Kelly’s mother, Sandra Fidoe, added: “The fact that she was bullied about it made it ten times worse for her and certainly for me. It bothered me.”
Kelly started seeing a doctor in her late teens, but nobody could diagnose her. After researching her symptoms and watching documentaries, she pushed doctors for an answer and was diagnosed with Trimethylaminuria in 2015.
Learning more about her condition led to her discovering that the copious amount of scented deodorants she was using and the relentless showering was actually making her skin react, which caused her odour to be stronger.
Now, Kelly uses Seba-Med body wash, which is PH neutral and much more sensitive for her skin.
She also takes regular medication including; daily B-2 tablets which enhances her body’s ability to metabolise the choline in her diet and Acidophilus, which is a pro-biotic that rebalances the bacteria throughout the body.
On top of that, she takes Activated Charcoal once a day after she has eaten to clean out her digestive system.
Thankfully for Kelly, she found love online 16 years ago with her now husband, Michael, who she says makes things easier for her.
Michael, 45, said: “Kelly’s smell has sometimes affected me in a negative manner but I haven’t said anything to Kelly. I’ve just kept it to myself.
“When we were living together at the start I did notice it.
“But it wasn’t straight away when we first started seeing each other – it was never a problem.
“I don’t believe she tried to hide it either.
“Kelly wasn’t that confident when we first met – and I think the best way of me helping her with the condition is to just be supportive about the condition.
“If that was me living with the condition, I think I would struggle to do as much as Kelly does.”
Kelly added: “Michael has helped me to cope by making me see the funny side of the condition.
“I am sure he won’t mind me saying this, but he produces his own smell anyway!”
Since working night shifts at The Royal Oldham Hospital, Kelly has recently been more open and honest about her condition with her closest work colleagues.
Faysal Bashir works alongside Kelly as a CT/MR radiographer.
He said: “You could trace Kelly’s smell up the corridor. It’s quite a strong, distinct smell you get from Kelly.
“When Kelly told me about her condition I didn’t take it in for some reason and so I have always called it ‘fishiyatitus.’
“I have had many complaints about Kelly’s smell to me and from a variety of staff in the department.
“It’s hard when you get these complaints as Kelly is a good friend.
“But working with Kelly for two years as my night buddy means we have a good communication where I could tell her to go and freshen up.”
Asha Feroz, a diagnostic radiographer who also works with Kelly, said: “Certain people do make comments.
“It was upsetting how people were dealing with it and at that point, Kelly wasn’t herself.
“I have got used to the smell. So it doesn’t affect my work at all.”
As much as Kelly’s friends and family have helped her through the hardships she has faced in life, it was the final diagnosis she received that allowed her to start accepting the condition with a sense of closure.
And now Kelly feels confident enough to raise awareness and speak about her condition in the hope that she can destigmatise it and people can tell her what is working to calm the smell.
Kelly said: “From watching documentaries, things started to fall into place and it sounded like it could be me when someone said it’s not just a fish odour.
“And ultimately I ended up being tested and it came back positive.
“I am more chilled about it now. I can’t say that if somebody complains tomorrow, I wouldn’t still find it a little bit cutting.
“But I deal with it by educating that person now.”
A man who tried to have sex with a corpse after digging into the grave was arrested when he fell asleep in the coffin, police in Cambodia confirmed today.
The 47-year-old man, named as Chin Chean, was caught when villagers saw his foot sticking out of the grave and told the family of the teenage girl whose body lay in the coffin.
Chin Chean told police that he started digging up the coffin at 10pm, the day after he had attended the funeral of the 17-year-old girl.
The Cambodia Daily reported that after digging down through the earth he reached the coffin and managed to open it.
He then admitted to police that he had tried to have sex with the body but because the coffin was too small he was not able to do so.
Then, he admitted, he fell asleep on top of the body.
'Villagers saw Mr Chean's foot by the grave at about 6am and told the deceased's family,' said police chief Keo Vutha of the Prey Poun community 103 miles south east of the capital, Phnom Penh.
'We don't know at this stage whether he knew the victim when she was alive,' said Mr Vutha.
But he said that Chin Chean was known to take drugs and commit unusual acts, such as running around the local pagoda naked.
'We are going to send Mr Chean to the district police for questioning before we sent him to court,' said a police spokesman.
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