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Alternative model for Alzheimer’s neurodegeneration
In recent debate over the FDA’s approval of the Alzheimer’s drug aducanumab, we’ve heard a lot about the “amyloid hypothesis.” In that context, it’s refreshing to learn about a model of Alzheimer’s neurodegeneration that doesn’t start with the pathogenic proteins amyloid or Tau. Instead, a new paper in Alzheimer’s & Dementia from Emory neuroscientist Shan Ping Yu and colleagues focuses on an unusual member of the family of NMDA receptors, signaling molecules that are critical for learning and memory. Their findings contain leads for additional research on Alzheimer’s, including drugs that are already FDA-approved that could be used preventively, and genes to look at for risk factors. “It’s not just another rodent model of Alzheimer’s,” Yu says. “We are emphasizing a different set of mechanisms leading to neurodegeneration.” Those mechanisms include alterations in calcium and neuronal hyperactivity, which occur first in this mouse model, rather than standard models that have clumps of amyloid or Tau as the primary drivers. GluN3A (in the diagram, NR3) is an inhibitory subunit within NMDA receptor assemblies, which function as glutamate-gated cation channels. GluN3A is a key regulator of neuronal activity and calcium homeostasis in both early and late life. For the last several years, Yu and his laboratory have been studying the NMDA receptor subunit GluN3A in the context of stroke and also brain development. According to their research, GluN3A acts like a control rod in a nuclear reactor, cooling down signaling in the brain so that things don’t overheat. It’s an inhibitory part of a receptor assembly that is usually stimulatory. Yu says GluN3A’s role in the adult brain is understudied, because it is generally thought to fade away after early development. Mice that are missing the gene for GluN3A get a benefit earlier in life, in that they have enhanced memory and spatial learning. But later on, the missing gene’s function catches up, and th

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