Alzheimer’s: Full Throttle in Neutral
16/12/2024
Aging increases the risk of Alzheimer’s disease. Despite the lack of effective treatments, early detection of symptoms can help patients and their families cope with the disease. Damage to the mechanisms that preserve proper aging begins long before symptoms appear, and even early detection cannot delay or halt the disease. A new study from Ben-Gurion University proposes a mechanism that explains why Alzheimer’s patients lose brain tissue over time, and identifies the factors involved in the process.
Sooner or later, most of us will reach old age. This is not only an optimistic description of a modern person’s lifespan, but also a complex societal and medical issue, stemming from the ripple effects of a large population reaching old-age[1]. Beyond wrinkles on the forehead and dentures, aging also increases the risk of neurodegenerative diseases such as Alzheimer’s Disease, which lead to dementia [2]. The incidence of dementia rises with the growing aging population, and yet, aside from delaying its progression or reducing suffering, we lack effective tools to tackle these diseases.
One of the challenges in studying neurodegenerative diseases is the difficulty to identify, the event that triggers the disease in time. The symptoms that are noticeable to the patient, their family, or their medical team usually result from processes that occurred much earlier within brain cells. Initially, these intracellular disturbances typically cause no symptoms; profound impact on quality of life only begins when damage to brain tissue has already accumulated [3]. For example, one hypothesis for the loss of brain tissue in Alzheimer’s is excessive activity and over-differentiation of the tissue—processes that should not occur in an adult brain.
To address this problem, aging researchers are developing models that simulate aging in the hope of finding mechanisms through which the disease might be influenced. The model can be anything from a single cell to a whole organism—that lacks a gene important for proper aging. For example, the gene that contains instructions for producing the enzyme SIRT6 has been extensively studied for its positive effect on healthy aging [4]. With age, the levels of SIRT6 in cells decrease, particularly in the brain, and even more so in Alzheimer’s patients, suggesting its key role in the progression of the disease.
But what if there is no SIRT6 in the brain at all? The laboratory of Dr. Debra Toiber at Ben-Gurion University is investigating this question. Dr. Toiber’s team showed that mice lacking the enzyme in the brain experience learning and memory problems and develop symptoms of a neurodegenerative disease [5], making these mice a good model for studying such conditions. To better understand the underlying cause, in a new study from the lab [6] the team examined which genes are activated or suppressed in the brains of mice lacking SIRT6.
Although all cells in the body share the same genetic information, what determines whether a cell becomes a neuron or a muscle cell, for example, is which genes are active—or inactive—in that cell. Because it is crucial that only the correct genes be active in each cell, there are protein systems whose role is to ensure that this happens [7]. Even after cells have differentiated into neurons, the set of active genes remains relatively defined. If the regulation is disrupted—for instance, if one of the regulatory proteins stops working—those cells can die or become cancerous.
An example of a protein that regulates neuronal genes is the RE-1 Silencing Transcription factor (REST) [8]. REST primarily functions in non-neuronal tissues, such as the skin, preventing them from differentiating into neural tissue. Yet, even in neural tissue, it plays an important role in preventing neurons from becoming overactive. REST has two main functions: first, to physically bind to the DNA at the locations of neuronal genes; and second, to recruit enzymes that condense the DNA in a manner that prevents gene expression. If these two conditions are not met, the gene continues to be active.
So what is the connection to SIRT6? In brains lacking SIRT6, there is significant activation of neuronal genes—that is, genes involved in neural activity or in the conversion of cells into neurons, which are normally regulated by REST. Given REST’s role in repressing neuronal genes, it was expected that its levels in the brains of SIRT6-deficient mice would be low. To the researchers’ surprise, REST levels in the brains lacking SIRT6 were significantly higher than in normal brains. When SIRT6 is reintroduced into cells, the levels of REST and the neuronal genes it regulates return to normal.
From the researchers’ results, it was concluded that:
🧠The presence of SIRT6 affects REST levels.
🧠The presence of SIRT6 is important for the proper function of REST in regulating neuronal genes.
So what could explain the activation of neuronal genes despite the high amount of REST in the cell? Which of REST’s two functions is compromised? The study’s results show that REST has no problem binding to neuronal genes in the absence of SIRT6 (which is good!), but its ability to recruit the enzymes that condense the DNA around the gene is diminished (which is really not good!). Therefore, REST is effectively in a “full throttle in neutral” state—without SIRT6, it cannot turn off the neuronal gene that is currently active, and the cell tries in vain to compensate by producing more REST.
Previous studies have linked poor REST activity to signs of Alzheimer’s, underscoring its importance in maintaining brain tissue. However, the reason for its reduced activity remained unclear. The current study provides evidence that SIRT6 is involved in regulating REST, and that low levels of SIRT6 in aging or Alzheimer’s can lead to abnormal REST activity and, ultimately, to damage to brain tissue. This discovery may contribute to a deeper understanding of the disease and might lead to the development of methods for early diagnosis and even intervention in its progression.
The author is one of the leading researchers of the study.
Hebrew editing: Galia Halevy-Sadeh
English editing: Elee Shimshoni
References:
Adam holds a Master’s degree in Biology from Ben-Gurion University. He is currently enrolled in an MD-PhD program in medicine and biomedical research at the Hebrew University, where he researches coping mechanisms for neurodegenerative diseases.
