Science: New Study Reveals the Mechanism of The Extensive Neuronal Loss in Alzheimer's Disease

This new research was published in the Science journal on September 15, 2023. It reveals the potential key factors behind neuronal loss in Alzheimer's disease, namely, an RNA gene called MEG3 and this process of necroptosis. These findings mark an important step toward further understanding the fundamental mechanisms of this complex.

A New Model for Unraveling the Alzheimer's Mystery

Most mouse models used in research couldn't naturally replicate these features, leaving scientists with questions about the relationship between these features and the progression of the disease.

To address this limitation, the researchers constructed a new model by implanting both healthy human neurons and mouse neurons into the brains of Alzheimer's disease mouse models simultaneously. The degeneration of these human neurons in the mouse brain closely resembled their counterparts in the human brain, enabling us to study them during the brain aging process and gain new insights into the basic processes of Alzheimer's disease.

It was observed that Alzheimer's disease characteristics, such as tau tangles and substantial neuronal loss, were only evident in human neurons and not in rodent neurons, mirroring the conditions observed in patients. This suggests that Alzheimer's disease may involve human-specific factors that standard mouse models cannot replicate.

The Culprit Behind Neuronal Loss

Using this new model, the authors delved deeper to discover the reasons behind neuronal death in Alzheimer's disease. They made a crucial breakthrough: in this model, they activated a pathway called necroptosis, leading to neuronal death, where necroptosis is a programmed cell death process.

Fig.1 Imaris 3D segmentation of AT8/PHF1/MC1-immunoreactive neurons reveals X34+ β-sheet fibrillary structures (intracellular Tau fibrils).¹

Furthermore, they found that in human neurons, a molecule called MEG3 significantly increased, which was also observed in Alzheimer's disease patients.

They also found that by reducing MEG3 and preventing necroptosis, they could, in turn, prevent cell death. More research is needed to understand how exactly MEG3 triggers necroptosis, but this finding represents a significant step forward in understanding how Alzheimer's disease leads to the loss of brain neurons.

Necroptosis has become an active area of drug development for conditions like cancer and amyotrophic lateral sclerosis (ALS). While there is still much to explore, these findings open a hopeful path for potential therapies for Alzheimer's disease and also offer promise for traditional treatments targeting amyloid and tau.

Reference

1. Balusu, Sriram et al. “MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease.” Science. 2023;381(6663):1176-1182. Distributed under Open Access License CC BY 4.0 without modification.