It's refreshing to read about an alternative model of Alzheimer's disease, one that doesn't involve Tau or amyloid. This is in the context of the FDA's recent approval of aducanumab.Shan Ping Yu, Emory neuroscientist and his colleagues have published a new paper in Alzheimer's & Dementia. It focuses on an uncommon member of the NMDA receptors family. This signaling molecules are crucial for memory and learning. These findings provide leads to further research into Alzheimer's. They include drug approvals that have been approved by the FDA that can be used to prevent it.Yu said, "It's more than a rodent model for Alzheimer's." "We emphasize a different set mechanisms that lead to neurodegeneration."These mechanisms include changes in calcium and neuronal activity, which are first observed in this mouse model rather than standard models with clumps amyloide or Tau.Yu and his lab have been studying the NMDA subunit GluN3A over the past several years. This has been in relation to stroke and brain development. Their research shows that GluN3A functions as a control rod in a nuclear reactor cooling down the brain's signaling so it doesn't heat up. It is an inhibitory component of a receptor system that is normally stimulatory.Yu believes that GluN3A's function in the adult brain has been understudied. It is thought to disappear after very early development. Mice lacking the gene for GluN3A have a greater chance of learning spatial and memory skills. Later, however, the missing gene's function is restored and the mice experience several symptoms of Alzheimer's disease, such as cognitive decline, amyloid/tau pathology, neurodegeneration, neuroinflammation and neurodegeneration.Yu states, "We have shown that almost all clinical symptoms and pathophysiology can spontaneously develop in the GluN3A knockout mice in an age-dependent fashion."Yu claims that he originally wanted to study GluN3A's role as a neurodegenerative factor because GluN3A knockout mice exhibit the early symptom Olfactory Dysfunction, which is common in Parkinson's and Alzheimer's patients. Yu and his colleagues have shown that gluN3A deficiency can lead to high calcium levels. These levels are normally tightly controlled and they are called "degenerative excitotoxicity."This is different from the excitotoxicity which is dangerous in stroke or traumatic brain injury. The "calcium hypothesis" is a well-known theory that neurodegeneration is caused by dysregulated calcium. Yu claims that the discovery of GluN3A's role in Alzheimer's disease is more related to the early stages, prior to amyloid plaque formation.The findings regarding GluN3A are a step in the right direction and warrant further investigation. The FDA approved memantine, an NMDA receptor antagonist, for Alzheimer's disease. However, it is not thought to cause any symptoms. Yu's lab demonstrated that memantine could be used to treat GluN3A mutant mice and prevent certain (but not all) cognitive impairments. Memantine, or a similar drug, could be used to prevent mild cognitive impairment and early Alzheimer's. Second, genetic variations of GluN3A have not been extensively studied in Alzheimer's. Studies on neuropsychiatric conditions show that a large percentage of people have mutations or deletions that affect GluN3A function.
