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A major new study on Alzheimer's disease provides previously unknown evidence of the origin of the disease that steals the brain. In addition, he suggests that some anti-HIV drugs called reverse transcriptase inhibitors may be immediately adapted to patients with Alzheimer's disease.
Led by scientists at the Sanford Burnham Prebys Medical Discovery Institute, the study shows that, as has long been suspected, Alzheimer's disease is a genetic disorder. But in almost all cases, it is not inherited. Instead, it occurs during the life of a patient through genetic rearrangements in neurons. DNA sequences are copied, modified and reinserted into the genome.
Genetic reorganization is not a random mutation, but a process that recombines DNA into different models. This redesign creates a mosaic of slightly different cells. The immune system uses this process to make antibodies, but this has never been seen in the human brain.
Inhibitors of reverse transcriptase could also ward off Alzheimer's disease in people with Down syndrome who develop Alzheimer's disease as they age, the study says.
Posted Wednesday in the newspaper Nature, the study can be viewed at j.mp/alzmosaic when it was posted.
Confirmation of findings is necessary, said Dr. Jerold Chun, the main author. But Chun says screening with anti-HIV drugs should begin immediately. Even a low degree of efficiency would be better than what is currently available.
The study combines single-cell and multi-cell analysis methods to examine 13 given human brains, some normal and some with Alzheimer's disease. His findings are consistent with the epidemiological data of elderly HIV-positive patients. They have been treated with reverse transcriptase inhibitors for decades and almost never develop Alzheimer's disease.
The first documented case of Alzheimer's in an HIV-positive individual was reported in 2016.
Dr. Paul Aisen, a long-time researcher on Alzheimer's disease and a clinical trial specialist, praised this praise. Aisen heads the USC Alzheimer's Therapeutics Research Institute in San Diego.
"The authors carefully demonstrate that there are many genetic alterations in the brain of Alzheimer's disease," Aisen said via e-mail.
"These are changes that occur with aging, rather than inherited genetic characteristics. Although it's an intriguing idea, the actual contribution of this age-related genetic change remains unclear. "
Fred "Rusty" Gage, president of the Salk Institute and brain specialist, said the study's findings support the claim that DNA sequences are copied and re-inserted into the neuronal genome.
"These results are quite striking and could have consequences for the diagnosis and progression of Alzheimer's disease," Gage told E-mail.
According to the Alzheimer's Association, approximately 5.7 million Americans have been diagnosed with Alzheimer's disease. This number is expected to double by 2060, according to the Centers for Disease Control and Prevention.
In recent years, Alzheimer's researchers have changed their view of the disease. They now say that Alzheimer's disease starts decades before the onset of symptoms. Eventually, the damage that destroys the brain becomes serious enough to affect cognition and memory.
Researchers are therefore increasingly looking for the earliest signs of Alzheimer's development before mental functions are affected.
The study traces the ultimate cause of genetic rearrangements, so blocking this reworking should block Alzheimer's disease.
Reworking can be likened to a copy-and-paste function in the affected neurons. But instead of making an exact copy, the process scrambles DNA segments and then reinserts them into the neuron's genome.
Normal brains also show genetic variation in individual cells. Research suggests that this condition is a normal part of brain development. Instead of having billions of identical neurons, everyone can vary slightly in a way that helps the brain function, Chun said.
This process goes wrong by producing the variations responsible for Alzheimer's disease, derived from a gene called APP. Some variants of this gene are strongly linked to Alzheimer's disease.
As the genes produce proteins, these rearrangements of the APP gene probably produce variations of toxic brain proteins called beta-amyloid, known for their involvement in Alzheimer's disease.
Some of these genetic variants are found in a very rare form of inherited Alzheimer's disease. Virtually everyone with these variations has Alzheimer's disease.
But this "family" form represents only a few percent of Alzheimer's cases. The vast majority of "sporadic" Alzheimer's cases show genetic tendencies, but are far from perfect correlation.
The study provides an explanation for sporadic Alzheimer's disease: these genetic changes occurring only in the brain, they do not occur during the sequencing of a person's genome.
In addition, this could explain the failures of amyloid treatment. Billions of dollars have been spent on developing drugs in the so-called "amyloid" hypothesis, which has hardly been demonstrated.
Chun explained that this could be due to the fact that amyloid drugs target a single molecular target and that there is molecular diversity in amyloid.
"What our data strongly support, is that there could be many, many other targets that would have been missed by these single molecular target therapeutics," Chun said.
This means that the hypothesis of amyloid is essentially correct, but that it is not deep enough, Chun said.
In an accompanying article, two UC San Diego Alzheimer's researchers stated that the study was also important because it provided "surprising existence" in the brain of what the & # 39; 39, so-called "somatic gene recombination".
"This phenomenon, previously reported only in the production of antibodies in immune cells, increases the diversity of proteins encoded by a given gene through DNA reorganization mechanisms," wrote Guoliang Chai and Joseph. G. Gleeson.
"The study suggests an unexpected mechanism in the development of Alzheimer's disease and broadens our understanding of the genesis of cerebral mosaicism," they wrote. "But if the accumulation of (recombinant DNA) in neurons is a cause or is caused by Alzheimer's disease, that remains to be proven."
Go to patients
Aisen warned that some studies indicate that Alzheimer's disease is more likely related to amyloid elimination defects, not to their manufacture.
"So while these new discoveries may have therapeutic implications, further clarification of this mechanism is needed," Aisen said.
Doctors could use anti-HIV drugs on patients with Alzheimer's as an "unspecified" use, said Chun. But that would require a thorough ethical review.
On the positive side, there is no treatment that affects the underlying neurodegeneration caused by Alzheimer's, and the safety profile of anti-HIV drugs is well known.
"Let's say it only works in 25% of cases, which still represents 1.5 million patients in the United States, not to mention their families," he said.
And even a modest effect of preserving cognition for a few years would mean a lot for these families, he said.
However, all medications are at risk and Alzheimer's patients tend to be older and may have other conditions.
Such non-compliant use is also not a scientific basis for the official approval of drugs for the treatment of Alzheimer's disease. This is the work of a well-designed clinical trial.
Designing such a trial will be complicated, Chun said. It is necessary to research accurately the patients who will probably benefit. Brain tests for amyloid deposits, which are now available, could help. But for now, it is not possible to actually detect pathological cerebral mosaicism in living people.
HIV link
The study indicates that variations related to the APP spread with the help of an enzyme called reverse transcriptase that HIV uses to replicate itself.
With the help of reverse transcriptase, HIV copies its genome into the genome of infected cells. Since it is part of the cell's DNA, the immune system is struggling to reach HIV. Inhibitors of reverse transcriptase, an integral part of HIV treatment, block this process.
Reverse transcriptase is also naturally found in the human body and probably plays an important role.
"Evolutionary biologists who have examined the human genome have estimated that almost half of our genome was created by reverse transcription," he said.
It's not clear if HIV reverse transcriptase is the same as the human version, Chun said. An element of the genome supposed to code for reverse transcriptase is called Line1.
"But there are 517,000 copies of Line1 in the genome," he said. "So which is the right one? And we also think that most of them are dead enzymes. "
The study follows a research published in 2015 by a team led by Chun, which revealed a neural mosaicism associated with Alzheimer's disease.
"The difference is that we've identified gene recombination here, so it's not a nonselective phenomenon on the fly," said Chun.
"In fact, it acts on at least this single gene (APP), which of course suggests that other genes could be affected. This is a concern for the future. "
Funding for the research was provided by the Shaffer Family Foundation; The Bruce Ford Foundation and Anne Smith Bundy; Sanford Burnham Prebys; National Institutes of Health and the Government of Taiwan.
Related reading
The amyloid hypothesis at the test
Replicas of villages for Alzheimer's patients planned in 100 cities
The Alzheimer's brain presents essential genetic differences
The major stages of research on Alzheimer's
Link of Alzheimer's disease and Down syndrome found
A scientist looking for the mystery of Alzheimer's
Help available for patients with Alzheimer's
Dr. George G. Glenner, 67, deceased; Research on Alzheimer's disease
(619) 293-1020
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