Alzheimer’s is the only disease among the top 10 causes of death in Americans that cannot be prevented, slowed or cured, according to the National Institute on Aging, and it’s estimated one in three seniors today will die with an Alzheimer’s disease or dementia diagnosis.
But IU biomedical researchers Hui-Chen Lu and Yousuf Ali have renewed hopes this month for the future of AD treatment by exposing the inner workings of NMNAT2, a brain enzyme.
Their study, published June 2 in the Public Library of Science Biology Journal, involved detailed analysis of brain tissue from organ donors and laboratory mice. Initially based out of Lu’s laboratory at Baylor University, the study was continued by Ali at IU’s Gill Center for Molecular Science.
Until now, the brain enzyme NMNAT2, nicotinamide mononucleotide adenylyltransferase, was understood to have a single agenda: the shielding of neurons from harmful stimuli. However, Lu and Ali unmasked a second critical role of NMNAT2: the dismantling of toxic T-protein buildup.
“(NMNAT2) exerts both an enzyme function to protect neurons from stress caused by over-excitation and a ‘chaperone’ function, shown for the first time in this study, to combat the misfolded proteins encountered by the brain during aging,” Lu said.
Repeated millions of times, this process shrinks the brain throughout time. That’s when the hallmark symptoms of AD begin to appear: confusion, an inability to recall new information and mood changes.
Lu’s team first took frozen cortical tissue from elderly organ donors who either had or did not have AD diagnoses at the time of their death.
In the brain cells of donors with an Alzheimer’s diagnosis, Lu’s team made a significant discovery: NMNAT2 levels were less than 50 percent of control levels obtained from non-AD patients.
All donors were enrolled in either Rush University’s Religious Orders Study or the Memory and Aging Project. In each, more than 500 senior citizens agree to annual medical and physical evaluations, including CT scans and cognitive memory testing, and brain donation after death.
Another section of the study involved injecting laboratory mice with toxic levels of Tau protein. These mice, essentially engineered to lose all memory and bodily control after six weeks, developed significantly fewer “tangles” and “plaques” within their neurons, pointing again to NMNAT2’s anti-Alzheimer’s agenda.
“A detailed knowledge of how NMNAT2 maintains neuronal integrity and its role in neuroprotection is critical not only for understanding normal brain function but also for providing necessary insights to assist in the development of new drugs,” Lu said. “Such studies are only possible through multidisciplinary team efforts, and we are extremely grateful for our wonderful collaborators and funding support.”
This study was sponsored by organizations such as the National Institute of Health and Alzheimer’s Association. Other collaborators were involved, including Rush University, Harvard University Medical School, MIT and the University of Texas.
