Anti-HIV Drugs May Help Alzheimer's Disease, Study Shows Foundational Cause Not Discovered

In addition, he suggests that some anti-HIV drugs called reverse transcriptase inhibitors can be immediately reused for patients with Alzheimer's disease.

Led by scientists at the Sanford Burnham San Diego Prebys Medical Discovery Institute, the study reveals that, as has long been suspected, Alzheimer's disease is a genetic disorder. But in almost all cases, it is not inherited. On the contrary, it occurs during the life of a patient by genetic rearrangements in neurons. DNA sequences are copied, modified and reinserted into the genome.

Genetic rearrangement is not a random mutation, but a process that recombines DNA into different patterns. This redesign creates a mosaic of slightly different cells. The immune system uses a similar process to make antibodies, but nothing like that has been observed 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 with age, the study said.

The study was published Wednesday in the newspaper Nature.

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 analytical methods with one and more cells to examine 13 given human brains, some normal, others 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 disease 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 Institute for Therapeutic Research of the University of Southern California on Alzheimer's in San Diego.

"The authors carefully demonstrate that there are many genetic alterations in the brain with 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 genetic change related to the current". age remains uncertain. "

Fred "Rusty" Gage, president of the Salk Institute and recognized brain expert, said the results of this study confirm the claim that DNA sequences are copied and reinserted 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, about 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 segments of DNA 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 awry in 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.

Since the genes produce proteins, these rearrangements of the APP gene probably produce variations of toxic brain proteins called beta-amyloid, known to be involved in Alzheimer's disease.

Some of these genetic variants are found in a very rare form of inherited Alzheimer's disease. Virtually all people with these variations suffer from Alzheimer's disease.

But this "family" form is only a few percent of all cases of Alzheimer's. The vast majority of cases of "sporadic" Alzheimer's show genetic tendencies, but are far from a perfect correlation.

The study provides an explanation for sporadic Alzheimer's disease: these genetic changes occurring only in the brain, they are not visible when a person's genome is sequenced.

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 proven.

Chun explained that this could be due to the fact that amyloid drugs target a single molecular target and that molecular diversity exists 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 amyloid hypothesis is essentially correct, but that it's not deep enough, Chun said.

In an accompanying article, two researchers from the University of California at San Diego Alzheimer's stated that the study was also important because it provided a "surprising existence" in the brain of what the 39, so-called "somatic gene recombination".

"This phenomenon, which has only been reported previously 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 a previously 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, this remains to be proven."

Aisen warned that some studies indicate that Alzheimer's disease is more likely related to defects in amyloid elimination, 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 disease as an "unspecified" use, said Chun. But that would require a thorough ethical review.

On the positive side, there is currently no treatment that affects the underlying neurodegeneration of 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, not all medications are risky and Alzheimer's patients tend to be elderly and may have other conditions.

Such non-compliant use also provides no scientific basis for the official approval of drugs for the treatment of Alzheimer's disease. This is the job of a well-designed clinical trial.

Designing such a trial will be complicated, Chun said. It is necessary to accurately find the patients who will probably benefit. Brain tests for amyloid deposits, which are now available, could help. But for the moment, it is not possible to detect pathological cerebral mosaicism in living beings.

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's 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 examined the human genome 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.

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 Taiwan government.

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An unprecedented recombination of DNA in the brain linked to Alzheimer's disease

More information:
Ming-Hsiang Lee et al. Gene Recombination of APP in Alzheimer's Disease and Normal Neurons, Nature (2018). DOI: 10.1038 / s41586-018-0718-6