Little deficiency appears as a hidden Alzheimer driver

What is the earliest spark that ignites the disease march of Alzheimer’s disease? Why do some people with Alzheimer’s changes in the brain never develop dementia? These questions have been confused by neuronicists for decades.

Now a team of scientists from Harvard Medical School could find the answer: Little deficiency in the brain.

Work, published in nature, shows for the first time that the lithium occurs naturally in the brain, protects it from neurodegeneration and maintains the normal function of all main types of brain cells. Discoveries – 10 years of creation – are based on a series of experiments at mice and on analyzes of human brain tissue and blood samples from people at various stages of cognitive health.

Scientists have found that the loss of lithium in the human brain is one of the earliest changes leading to Alzheimer’s disease, while in mice, similar impoverishment of lithium, accelerated brain pathology and a decrease in memory. The team also stated that reduced lithium levels result from binding with amyloid plates and handicapped echoys in the brain. In the final set of experiments, the team stated that a new lithium compound that avoids the interception of amyloid tiles will restore memory of mice.

“The idea that lithium deficiency may cause Alzheimer’s disease is new and suggests a different therapeutic approach,” said the elderly author Bruce Yankner, a professor of genetics and neurology at the Blavatnik Institute in HMS, who in the 1990s was the first to show that amyloid beta is toxic.

The study increases the hope that one day scientists could use lithium to treat the disease in full, instead of focusing on one aspect such as beta amyloid or tau.

One of the main discoveries in the study is that when amyloid beta begins to form settlements in the early stages of dementia in both humans and mouse models, it is associated with lithium, reducing the function of lithium in the brain. Lower lithium levels affect all main types of brain cells, and mice cause changes to summarize Alzheimer’s disease, including memory loss.

The authors identified the class of lithium compounds that can avoid amyloid beta capture. Treatment of mice with the strongest compound causing amyloid, called lithium-orotate, reversed the pathology of Alzheimer’s disease, prevented brain cell damage and memory was restored.

Although the findings should be confirmed in humans through clinical examinations, they suggest that measuring lithium levels can help in the Alzheimer’s early disease. In addition, discoveries indicate the importance of testing lithium compounds resulting from amyloid in treatment or prevention.

Other lithium compounds are already used to treat bipolar disorder and serious depressive disorders, but they are administered in much higher concentrations that can be toxic, especially for the elderly. Yankner’s syndrome stated that Lit-Orotate is effective in one thousandth dose-which to follow the natural level of lithium in the brain. Mice treated by almost all adult life did not show evidence of toxicity.

“You have to watch out for extrapolation from mouse models and you never know until you try it in a controlled clinical trial,” said Yankner. “But so far the results are very encouraging.”

Lithuanian exhaustion is an early sign of Alzheimer’s disease

Yankner became interested in a solid, using it to study protein neuroprotective. Finding out if the lithium occurs in the human brain and whether its levels change as neurodegeneration and progress developed, it required access to the brain tissue, in which you can usually not access live people.

Thus, the laboratory established cooperation with the Rush memory and aging project in Chicago, which has a brain tissue bank transferred by thousands of study participants in the full spectrum of cognitive health and diseases.

Having this range was critical because an attempt to examine the brain at the late stages of Alzheimer is like looking at the battlefield after the war, said Yankner; There is a lot of damage and it’s hard to say how it all began. But at the early stages: “Before the brain is seriously damaged, you can get important tips,” he said.

The team, led by the first author of Liviu Aron, a senior research collaborator at the Yankner laboratory, used an advanced type of mass spectroscopy to measure trace levels of about 30 different metals in the brain and blood healthy, those at an early stage of dementia called mild cognitive impairment, and those with an advanced Alzheimer.

Lit was the only metal that had clearly different levels between groups and changed at the earliest stages of memory loss. His levels were high in healthy cognitive donors, but significantly decreased in people with mild impairment or a full outbreak of Alzheimer’s disease.

The team repeated their findings in samples obtained from many brain banks throughout the country.

The results unify ten -year observations in patients, ensuring a new theory of the disease and the new strategy of early diagnosis, prevention and treatment.

Influencing 50 million to 400 million people around the world, Alzheimer’s disease includes a number of brain abnormalities – such as clumps of beta amyloid proteins, neurofibrillar tau tau tau and protein protein loss called rest – but they never explained the full history of the disease. For example, some people with such irregularities do not show signs of cognitive inheritance. And recently developed treatments focused on beta amyloid usually do not reverse memory loss and only slightly reduce the rate of decline.

It is also obvious that genetic and environmental factors affect Alzheimer’s risk, but scientists did not come up with why some people with the same risk factors develop the disease, while others do not.

Lit, the authors of the research, as the authors of the research say, can be a critical missing link.

Observation has adapted to previous population research showing that a higher level of lithium in the environment, including in drinking water, followed with lower indicators of dementia.

But the new study went beyond directly observing liters in the brains of people who did not receive lithium as treatment, establishing a range that is normal levels, and showing that litter plays an important role in brain physiology.

“Litu turns out to be like other nutrients that we get from the environment, such as iron and vitamin C” – said Yankner. “For the first time, whoever showed that lithium exists at a natural level that is biologically significant, not giving it as a drug.”

Then Yankner and colleagues went a step further. They showed at mice that the exhaustion of lithium is not only associated with Alzheimer’s disease – it helps them.

Loss of lithium causes the scope of changes related to Alzheimer’s disease

Scientists have found that feeding healthy mice, a diet with limited liters reduced the level of lithium lithium to a level similar to that of patients with Alzheimer’s disease. It seemed that it accelerates the aging process, causing encephalitis, the loss of synaptic connections between neurons and cognitive decline.

In the Alzheimer’s mouse models, the exhausted lithium dramatically accelerated the creation of amyloid-beta tiles and structures, which resemble neurofibrillary faints. Lithuania’s exhaustion also activated inflammatory cells in the brain called microglejs, impairing their ability to degrade amyloid; caused the loss of synapses, axons and myeline protecting neuron; and an accelerated cognitive decline and memory loss – all features of Alzheimer’s disease.

Mouse experiments also revealed that lithium has changed the activity of genes, which are known to increase or lower risk of Alzheimer’s disease, including the most famous APOE.

Supplementing the lithium by giving orotate lithium mice in their water reversed damage associated with the disease and restored memory function, even in older mice with advanced disease. In particular, maintaining a stable level of lithium in an early period of life prevented the beginning of Alzheimer’s disease – a discovery that confirmed that lithium drives the disease process.

“It impresses me the most in the lithium, there is a widespread impact on various manifestations of Alzheimer’s disease. I have really not seen anything similar to the fact that these are all years of work on this disease,” said Yankner.

A promising way to treat Alzheimer

Several limited clinical trials of the lithium of Alzheimer’s disease showed some effectiveness, but the lithium compounds they use – such as clinical standard, lithium carbonate – can be toxic to aging people in high doses usually used in the clinic.

New studies explain why: amyloid beta sequested these other lithium compounds before they could work. Yankner and colleagues found a lithium Orotate, developing a screening platform that searches the library of compounds for those that can bypass amyloid beta. Other researchers can now use the platform to search for additional lithium compounds that can be even more effective.

“One of the most galvanized findings for us was that in this extremely low dose there were deep results,” said Yankner.

In the case of repeated in further studies, scientists say that lithium screening through routine blood tests may one day offer a way to identify people at risk of Alzheimer’s disease that would benefit from treatment to prevent or delay the disease.

Yankner said that the study of lithium levels in people resistant to Alzheimer’s disease can help scientists determine the target level that they can help patients prevent the disease.

Since Lit has not yet been demonstrated safe or effective in the protection of neurodegeneration in humans, Yankner emphasizes that people should not take lithium compounds themselves. But he expressed cautious optimism that Lit -Orotate or a similar relationship would be promoted to clinical trials in the near future and may eventually change the history of Alzheimer’s treatment.

“I hope that Lit will do something more fundamental than anti-amyloid or anti-tu therapies, not only reducing, but by reversing the cognitive fall and improving the life of patients,” he said.