Alternative model of Alzheimer’s disease emphasizes different sets of mechanisms that lead to neurodegeneration

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In the context of the recent debate over the FDA approval of aducanumab, it is refreshing to discover a model of Alzheimer’s neurodegeneration that does not start with the pathogenic proteins amyloid or Tau.

A new paper in Alzheimer’s and dementia neuroscientist Emory Shan Ping Yu and colleagues focuses on an unusual member of the NMDA receptor family, signaling molecules essential for learning and memory. Their findings contain leads for further research into Alzheimer’s disease, including drugs already approved by the FDA that could be used preventively, and genes to look for risk factors.

It’s not just another rodent model of Alzheimer’s disease. We focus on a different set of mechanisms leading to neurodegeneration. “

Shan Ping Yu, Neuroscientist, Emory Health Sciences

These mechanisms include alterations in calcium and neuronal overactivity, which occur first in this mouse model, rather than in standard models that have amyloid or Tau clusters as the primary drivers.

For several years, Yu and his laboratory have been studying the NMDA GluN3A receptor subunit in the context of stroke and brain development. According to their research, GluN3A acts like a control bar in a nuclear reactor, cooling signaling in the brain so things don’t overheat. It is an inhibitory part of a set of receptors which is generally stimulatory.

Yu says the role of GluN3A in the adult brain is under-studied, as it is generally believed to fade after early development. Mice lacking the GluN3A gene have an advantage earlier in life, in that 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 disease, including odor deficits, cognitive decline, neurodegeneration and neuroinflammation, and possibly amyloid / tau pathology.

“We show that virtually all of the clinical symptoms and pathophysiology developed spontaneously in the GluN3A knockout mice in an age-dependent manner,” said Yu.

Yu says he was originally motivated to examine the role of GluN3A in neurodegeneration because GluN3A knockout mice develop the early symptom of olfactory dysfunction, which is commonly seen in patients with Alzheimer’s and Alzheimer’s disease. Parkinson’s. In the present article, Yu and his colleagues show that the loss of GluN3A results in high calcium levels, normally tightly regulated, and what they call “degenerative excitotoxicity”.

This is distinct from excitotoxicity which is harmful in traumatic brain injury or stroke – milder and more chronic. They link hyperactivity and inflammation to the “calcium hypothesis” for Alzheimer’s disease – a well-established idea that deregulated calcium causes neurodegeneration. Yu says their discovery of GluN3A’s role is more about the early stages of the disease, before amyloid plaque forms.

Looking ahead, the GluN3A results have implications for further investigation. First, memantine, an inhibitor of the NMDA receptor, is approved by the FDA for Alzheimer’s disease, but it is generally believed to only have an effect on symptoms. Yu’s lab has shown that they can prevent some (but not all) deficits by treating GluN3A mutant mice with memantine.

Perhaps memantine or a similar drug could play a preventative role if given to people with mild cognitive impairment or early-onset Alzheimer’s disease? Second, genetic variations in GluN3A have hardly been studied in Alzheimer’s disease, and studies of other neuropsychiatric conditions suggest that a significant percentage of people carry mutations or deletions affecting the function of the GluN3A gene.

Source:

Journal reference:

Zhong, W., et al. (2021) Pathogenesis of sporadic Alzheimer’s disease by deficiency of the NMDA GluN3A receptor subunit. Alzheimer’s and dementia. doi.org/10.1002/alz.12398.



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