Researchers from the Autonomous University of Madrid (UAM) and CSIC have studied the effect of lamivudine, a drug used in the treatment of HIV, in a transgenic model of Alzheimer’s disease. The results, published in the International Journal of Molecular Sciences, suggest that retranscriptase inhibitors may be a promising strategy to be developed in the field of neurodegenerative diseases.
Researchers at the Severo Ochoa Center for Molecular Biology (CBMSO), a joint center of the Autonomous University of Madrid (UAM) and the Spanish National Research Council (CSIC), have discovered that lamivudine (3TC), a drug used in HIV therapy, can have a positive effect and slow the progression of Alzheimer’s disease (AD).
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, an increase in survival of 30%.
The researchers also identified in mice treated with 3TC improvements in several memory tests, as well as a decrease in histopathological hallmarks of AD, such as levels of hyperphosphorylated tau protein and associated neuroinflammation.
These results, published in the International Journal of Molecular Sciences, position retranscriptase inhibitors used in HIV patients as a promising strategy to be developed in the field of neurodegenerative diseases and, probably, in aging.
Leaping" genes, Alzheimer’s disease and aging
Transposons (TEs), also known as "jumping" genes or mobile elements, are DNA sequences that constitute more than 50% of the human genome. These elements, which have been self-amplifying in mammalian genomes throughout evolution, are divided into two major groups.
On the one hand, there are the DNA transposons that are mobilized through the "cut-and-paste" mechanism, although these are already inactive in humans. On the other hand, retrotransposons (RTE) are mobilized through the "copy-and-paste" mechanism by means of 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 about 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 during much of development, are reactivated as cellular surveillance and defense mechanisms begin to fail as a result of aging. This process has been demonstrated in a model of neurodegeneration in Drosophila (fruit flies).
Since aging is the main risk factor in neurodegenerative diseases such as AD, the study of retratransposition processes under these conditions may shed light on these pathologies and reveal how to achieve healthy aging.
In this context, the work developed at the Center for Molecular Biology Severo Ochoa (CBMSO) by researchers from the UAM and CSIC, has been based on analyzing the effects that pharmacological inhibition of the retrotranscriptase of RTE has on the progression of the disease in an animal model of Alzheimer’s disease.
On the other hand, lamivudine (3TC), a cytidine analogue that inhibits retrotranscriptases and is mainly used in HIV therapy, is a drug that shows an acceptable safety profile in long-term treatment in humans.
Previous observations in Drosophila models had shown that 3TC suppresses ET mobilization. Although these previous observations pointed to the therapeutic potential of 3TC for the treatment of neurodegenerative diseases, it had not been studied in a mammalian model of AD until now.
Alzheimer’s disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, the main risk factor being age.
Most cases of AD are sporadic, with no known underlying cause, and only 5% of cases are familial cases in which the genetic cause is known and therefore heritable.
Bibliographic reference:
Vallés-Saiz, L., Ávila, J., Hernández, F., 2023. Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice International Journal of Molecular Sciences 24, no. 13: 11144. doi: 10.3390/ijms241311144.
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