In the context of the recent FDA approval of aducanumab debate, it is refreshing to learn of a model of Alzheimer’s neurodegeneration that does not start with the pathogenic proteins amyloid or tau.
A new article in Alzheimer’s & Dementia by Emory neuroscientist Shan Ping Yu and colleagues focuses on an unusual member of the family of NMDA receptors, signaling molecules critical to learning and memory. Their results provide clues for further research on Alzheimer’s, including FDA-cleared drugs that could be used preventively and genes to look for risk factors.
“It’s not just another rodent model of Alzheimer’s disease,” says Yu. “We emphasize a different set of mechanisms that lead to neurodegeneration.”
These mechanisms include changes in calcium and neural hyperactivity that appear first in this mouse model, rather than in standard models that have amyloid or tau clumps as the primary drivers.
Yu and his laboratory have been studying the NMDA receptor subunit GluN3A in connection with stroke and brain development for several years. According to their research, GluN3A acts like a control rod in a nuclear reactor, cooling the signals in the brain so that things do not overheat. It is an inhibitory part of an array of receptors that is normally stimulatory.
Yu says the role of GluN3A in the adult brain is under-researched as it is widely believed to go away after early development. Mice lacking the gene for GluN3A benefit earlier in life because they have improved memory and spatial learning. But later, the function of the missing gene catches up, and the mice develop several features of Alzheimer’s, including olfactory deficits, cognitive decline, neurodegeneration and neuroinflammation, and finally amyloid / tau pathology.
“We show that in the GluN3A knockout mouse practically all clinical symptoms and pathophysiology developed spontaneously, depending on age,” says Yu.
Yu says he was originally motivated to investigate GluN3A’s role in neurodegeneration because the GluN3A knockout mice develop the early symptom of an olfactory disorder that is common in Alzheimer’s and Parkinson’s patients. In the current paper, Yu and colleagues show that the loss of GluN3A leads to increased calcium levels, which are normally tightly regulated, in what they call “degenerative excitotoxicity”.
This is different from excitotoxicity, which is harmful in traumatic brain injury or stroke – milder and more chronic. They combine hyperactivity and inflammation with the “calcium hypothesis” for Alzheimer’s disease – an established notion that dysregulated calcium drives neurodegeneration. Yu says her discovery of the role of GluN3A relates more to the early stages of the disease, prior to amyloid plaque formation.
Looking ahead, the results on GluN3A will have implications for further research. First, the NMDA receptor inhibitor memantine is FDA approved for Alzheimer’s, but it is widely believed that it only has an effect on symptoms. Yu’s lab showed that they could prevent some (but not all) of the deficits by treating GluN3A mutant mice with memantine. Perhaps memantine or a similar drug could play a preventive role when given to people with mild cognitive impairment or early Alzheimer’s disease? Second, genetic variations of GluN3A in Alzheimer’s disease have barely been studied, and studies on other neuropsychiatric disorders suggest that a significant percentage of people carry mutations or deletions that affect GluN3A gene function.
###
Yu and co-senior writer Ling Wei are both in the anesthesiology department at Emory, along with senior author Weiwei Zhong’s research associate, who now works at Thermo Fisher. The research was supported by the National Institute of Neurological Disorders and Stroke (NS057255, NS099596, NS091585), the Veterans Administration (RX001473), the O.Wayne Rollins Endowment Fund, and the John E. Steinhaus Endowment Fund.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of press releases sent to EurekAlert! by contributing institutions or for the use of information via the EurekAlert system.
Comments are closed.