Adnkronos Rome, October 7 (Adnkronos Salute) – In the complex puzzle of Alzheimer's disease, a crucial piece has just been put into place. An international research team, led by scientists from the Department of Experimental Medicine and the Daniel Bovet Neurobiology Research Center (CRIN) at Sapienza University of Rome, has discovered a sophisticated 'crosstalk'—a molecular dialogue—between two key mechanisms that regulate the expression of our genes: DNA methylation and microRNAs.
This dialogue, described today in 'Alzheimer's & Dementia,' the official journal of the Alzheimer's Association, directly controls the production of the beta-amyloid protein, whose accumulation in the brain in the form of senile plaques is considered the most significant event in the disease.
For decades, Alzheimer's research has focused primarily on eliminating beta-amyloid plaques, often with disappointing results. Many drugs designed for this purpose have proven ineffective in clinical trials. For this reason, the scientific community is increasingly shifting its attention to the "upstream" mechanisms, namely how to regulate the production of this protein, which is "toxic" but still has a physiological role. "Beta-amyloid is produced by two enzymes, veritable 'molecular scissors,' which cut a larger precursor protein. These enzymes are encoded by the Psen1 and Bace1 genes. The Sapienza research team, coordinated by Professor Andrea Fuso, had previously demonstrated that Psen1 production could be reduced through an epigenetic mechanism known as DNA methylation. Methylation acts like a switch: when a chemical group (methyl) is added to the DNA, the gene is 'silenced,'" the statement reads. However, it remained unclear how Bace1, the other key molecular scissors, was regulated.
The new study reveals that BACE1 regulation is more complex and occurs indirectly. Here's the chain of command discovered by the researchers: "DNA methylation doesn't directly affect BACE1, but controls the expression of a small regulatory RNA, a microRNA called miR-29a. MicroRNAs are molecules that function as precision 'silencers': they bind to specific genes and prevent their translation into proteins. In turn, miR-29a targets the BACE1 gene. When miR-29a levels are high, BACE1 production is repressed, and consequently, the production of beta-amyloid is also reduced. The most surprising result—the study states—is that methylation of the gene that produces miR-29a, rather than turning it off, increases its expression. This is a counterintuitive epigenetic mechanism that reveals a new, sophisticated logic of cellular control." In summary, DNA methylation regulates the production of beta-amyloid through two pathways: a direct one, by silencing the Psen1 gene, and an indirect one, by activating the 'protective' microRNA miR-29a which in turn turns off the Bace1 gene.
"This discovery is like finding the key to understanding a process of which we previously only saw the final result," explains Andrea Fuso, coordinator of the study. "We've understood that the cell doesn't use a single switch, but an integrated control panel in which DNA and microRNA communicate to fine-tune a vital process, the alteration of which is associated with disease. This is crucial for approaching a highly multifactorial disease. It's a breakthrough in understanding the complex biomolecular mechanisms of Alzheimer's."
This discovery is not only a fundamental advance in knowledge, but also opens up concrete prospects. New therapeutic strategies: "The entire system is modulated by a biochemical cycle known as 'one-carbon metabolism,' a cellular process influenced by nutrients such as B vitamins and molecules such as S-adenosylmethionine (SAM). The study demonstrates that providing SAM increases methylation, activates miR-29a, and reduces the production of beta-amyloid. This—the study continues—suggests that "methylating" molecules could be used not as simple supplements, but as actual epigenetic drugs capable of helping prevent or slow disease progression."
Epigenetics at the center. "In addition to SAM, other interventions are being studied that appear to be able to modulate the epigenetic response of cells, such as vitamin K2 and factors present in stem cell extracts and fish eggs (stamisomes). The importance of this research lies in the fact that epigenetic factors also appear to regulate other molecular processes associated with the disease, such as neuroinflammation, oxidation, and the function of the blood-brain barrier," the researchers reveal.
Potential biomarkers. "The methylation profile of Psen1 and levels of miR-29a could become an early marker of disease or treatment response, measurable with a simple blood test," the study suggests. "The same research group has recently developed a biosensor capable of easily measuring their levels in circulating fluids." The study was conducted thanks to an international collaboration involving Sapienza University, the University of Naples "Federico II," and the University of Barcelona.
"Understanding how our genes are turned on and off, with the possibility of intervening to regulate these mechanisms, is one of the most promising frontiers of modern medicine," concludes Fuso. "With this work, we have added a crucial piece that not only brings us closer to understanding Alzheimer's, but also provides us with new and promising targets for action."