The population of the world is steadily living longer, increasing the likelihood of one in three developing a form of Alzheimer’s in their lifetime. Much work has been done to combat this debilitating disease, but as of yet, there is no cure. After a decade of work a team led by Hôpital Maisonneuve-Rosemont researcher and Université de Montréal associate professor Dr. Gilbert Bernier has shed promising light on the origin of the most common and prevalent form of Alzheimer’s hoping to someday help mitigate or even reverse the progress of the disease.
There are genetic variables when it comes to being diagnosed with this disease, but age is the principal risk factor. Many researchers are trying to better understand the genetic and pathophysiological risks, but few studies have focused on the origin of Alzheimer’s and its relationship with the aging of the brain.
Working from the idea that the most prevalent form of Alzheimer’s disease is not genetic but instead epigenetic, Dr. Bernier and his team carried out an extensive scientific investigation to better understand the role of a specific gene, BMI1, in the onset and development of the disease.
In a study published in 2009, researchers found that, in mice models, the mutation of the BMI1 gene triggered an accelerated and pathological aging of the brain and eyes. Based on this finding, Dr. Bernier’s team deduced that if the BMI1 gene stopped functioning in a human, it would also cause accelerated aging of the brain and the development of conditions related to Alzheimer’s disease.
By comparing the brains of deceased Alzheimer’s patients (taken from samples in the Douglas Bell Canada Brain Bank) with those of deceased non-Alzheimer’s patients of the same age, the team observed a marked decrease of the BMI1 gene only in patients who died of the disease. To verify that this decrease was not simply a consequence of the disease, the researchers repeated the process with patients who died of early onset Alzheimer’s disease, which is a genetic and much rarer form of the that strikes before the age of 50 and sometimes even before 40. The researchers discovered that there was no change in BMI1 gene expression in these cases.
In a third step, the team examined the brains of individuals who died from other aging-related dementias, and once again observed no change in BMI1 gene expression. Finally, using a complex method, the researchers recreated in the laboratory, neurons found in Alzheimer’s disease patients and healthy individuals. Once again, BMI1 gene expression only decreased in neurons of Alzheimer’s-disease patients.
The team concluded that the loss of BMI1 gene expression in the brains and neurons of patients with the common form of Alzheimer’s was not a consequence of the disease and could, therefore, be the cause.
This led to the researchers wanting to test their hypothesis that the loss of BMI1 plays a direct role in the development of Alzheimer’s disease. To do so, they created healthy human neurons in the lab. Once the neurons reached maturity, they deactivated the BMI1 gene using a genetic method. The results were remarkable. All the neuropathological markers of Alzheimer’s were reproduced in the lab, concluding to the researchers that the loss of BMI1 function in human neurons was enough to activate the disease.
Encouraged by their unexpected findings, the researchers also ran molecular studies to understand how the loss of BMI1 triggers the disease. These studies revealed that the loss of BMI1 causes an increase in production of beta-amyloid and tau proteins and a decrease in the neurons’ natural capacity to eliminate toxic proteins.
The researchers believe that the restoration of BMI1 gene expression in the neurons of Alzheimer’s disease patients in the preliminary stages could mitigate or even reverse the progress of the disease. This provides hope for the future to patients that are ravaged by this disease and for their caregivers alike.