Alzheimer’s disease (AD) is a devastating condition that results in cognitive impairment, loss of executive functions and dementia. It is estimated that 36 million people world-wide suffer from dementia. In Canada alone, 564 000 people have dementia with 25 000 people dying as a result each year, creating an annual financial burden of $10.4 billion. In 15 years, this number is projected to double. Despite substantial efforts in drug development and increased understanding of pathology, currently no disease modifying therapy is available and treatment of Alzheimer’s disease remains symptomatic.
Dr. Hemant Paudel, associate professor in the Department of Neurology at McGill University’s Faculty of Medicine has been studying Alzheimer’s disease in his laboratory for decades. Now, as part of a new study led by Dr. Paudel, who is also Senior Investigator, Bloomfield Centre for Research in Aging, Lady Davis Institute at the Jewish General Hospital, and published in the Journal of Biological Chemistry, he and his team have unraveled an important clue to dealing with the cause of beta secretase activation, which has shown to be over activated in the brains of those suffering from AD.
“Tangles and plaques are the two characteristic neuropathological lesions found in the brains of patients suffering from AD,” explains Dr. Paudel. Tangles are found inside the nerve cells in the form of twisted fibers and are formed by abnormal hyper phosphorylation – containing more phosphates than the normal tau of a healthy brain. Hyperphosphorylated tau is unable to provide mechanical support to neurons.
On the other hand, plaques are found outside and between the nerve cells and are thought to interfere with nerve cell communication, to trigger inflammation and to promote cell demise. Plaques are formed from a small peptide called beta amyloid by the sequential actions of two enzymes called beta secretase-1 and gamma secretase. “A number of studies have determined that beta secretase is somehow over activated in the Alzheimer’s disease brain, which leads to excess production of beta amyloid peptide and plaque formation,” says Dr. Paudel. “What activates beta secretase in AD patients had remained, until now, a mystery.”
In 2011, Dr. Paudel and his team found that the level of a protein called early growth response 1 (Egr-1) was significantly elevated in the autopsied brains of patients suffering from Alzheimer’s disease. Of note, they also found that Egr-1 promotes AD-like tau protein hyperphosphorylation in mouse brain. “In this new study, we discovered that mice that do not express Egr-1 have significantly reduced levels of beta secretase-1,” notes Dr. Paudel. “By using various molecular biology techniques, we determined that in neurons, Egr-1 activates beta secretase-1 and by doing so causes accumulation of beta amyloid. Our data indicate that Egr-1 is the elusive activator of beta secretase-1 during the progression of AD.”
The researchers further examined mice that do not express Egr-1 and found that these mice had significantly reduced levels of beta amyloid and phosphorylated tau. Alzheimer’s disease can be divided into two categories: familial and sporadic. Familial AD accounts for less than 1% of all cases with onset occurring between the ages of 55-65 due to genetic predisposition.
Most AD cases, however, are sporadic and often begin at age 65 or older. The cause of sporadic AD is not known, however all AD patients have excess hyperphosphorylated tau and beta amyloid. “Our data indicate that by inhibiting Egr-1 alone, it will be possible to reduce the level of both beta amyloid and phosphorylated tau in the brain of all AD patients” explains Dr. Paudel. “Egr-1 therefore offers a new potential therapeutic target for the treatment of AD.”
This study was supported by funding from the Canadian Institute of Health Research and Alzheimer’s Society of Canada
“Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain.” Pauel, HK, et al. The Journal of Biological Chemistry, 14 October 2016 doi: 291(42):22276-22287
October 21, 2016