2023-09-07 15:15:12
Alzheimer’s disease is a progressive neurodegenerative disorder, with age being the main risk factor. Most cases of Alzheimer’s disease are sporadic, with no known underlying cause, and only 5% of cases are familial cases in which the genetic cause is known and, therefore, are heritable.
Scientists have studied the effect of lamivudine, a drug used in the treatment of HIV (the virus responsible for AIDS), in a transgenic model of Alzheimer’s disease.
The results suggest that retranscriptionase inhibitors may be a promising strategy to develop in the field of neurodegenerative diseases.
The study is the work of researchers from the Severo Ochoa Molecular Biology Center (CBMSO), a joint center of the Autonomous University of Madrid (UAM) and the Higher Council for Scientific Research (CSIC), in Spain all of these entities.
Laura Vallés-Saiz, Jesús Ávila and Félix Hernández, all from CBMSO, have discovered that lamivudine (3TC), a drug used in HIV therapy, can have a positive effect and slow the progression of Alzheimer’s disease.
Specifically, after treating Alzheimer’s disease model mice with 3TC for three months, the researchers observed a remarkable improvement in the phenotype of the animals and, especially, a 30% increase in survival.
The researchers also identified improvements in several memory tests in mice treated with 3TC, as well as a decrease in histopathological hallmarks of Alzheimer’s disease, such as levels of hyperphosphorylated tau protein and associated neuroinflammation.
These results position retranscriptase inhibitors used in patients with HIV as a promising strategy to develop in the field of neurodegenerative diseases and, probably, in aging.
Artistic recreation of brain cells deteriorating due to Alzheimer’s disease. (Illustration: Amazings/NCYT)
“Jumping” genes, Alzheimer’s and aging
Transposons (TEs), also known as “jumping” genes or mobile elements, are DNA sequences that make up more than 50% of the human genome. These elements, which have been self-amplifying in mammalian genomes throughout evolution, are divided into two large groups.
On the one hand, there are DNA transposons that are mobilized by the “cut and paste” mechanism, although these are already inactive in humans. On the other hand, retrotransposons (RTEs) are mobilized through the “copy and paste” mechanism using an RNA intermediate, a process known as retrotransposition, which requires an enzyme called retrotranscriptase. Of these, the most important are the LINE-type retrotransposons.
LINE-type RTEs represent around 21% of the genome, but only a small percentage of them are sequences capable of “jumping” and carrying out the entire transposition process and inserting a new copy of the transposon into the genomic DNA. These new insertions are a major source of mutations and cellular genomic instability.
Previous studies have proposed that TEs, silenced for much of development, are reactivated as cellular defense and surveillance mechanisms begin to fail as a result of aging. Process that has been demonstrated in a neurodegeneration model in Drosophila (fruit fly).
Given that aging is the main risk factor in neurodegenerative diseases such as Alzheimer’s disease, the study of retrotransposition processes in these conditions can provide new and revealing data on these pathologies and reveal how to achieve healthy aging.
In this context, the work developed at the Severo Ochoa Molecular Biology Center by researchers from the UAM and the CSIC has been based on analyzing the effects that the pharmacological inhibition of the reverse transcriptase of the RTE has on the progression of the disease in a animal model of Alzheimer’s disease.
On the other hand, lamivudine (3TC), a cytidine analogue that inhibits reverse transcriptases and is mainly used in HIV therapy, is a drug that shows an acceptable safety profile in long-term treatments in humans.
Previous observations in Drosophila models had shown that 3TC suppresses TE mobilization. Although these previous observations pointed to the therapeutic potential of 3TC for the treatment of neurodegenerative diseases, until now it had not been studied in a mammalian model of Alzheimer’s disease.
The study is titled “Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice.” And it has been published in the academic journal International Journal of Molecular Sciences. (Source: UAM)
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