MIT researchers have identified a subset of neurons in the hypothalamus’ mammillary body that are particularly susceptible to neurodegeneration and hyperactivity in Alzheimer’s disease. This region may contribute to some of the earliest symptoms of Alzheimer’s, such as memory loss, making it a good target for potential new therapies for the disease.
For their work, published in the journal Science Translational Medicine, researchers discovered that the lateral mammillary body neurons, not those in the medial mammillary body, became hyperactive and underwent neurodegeneration in Alzheimer’s disease. They found that the damage leads to memory impairments and that this damage emerges early on in Alzheimer’s progression before amyloid plaques begin to develop.
Using a mouse model with five genetic mutations linked to early-onset Alzheimer’s in humans, the team saw that these mice showed much more hyperactivity in lateral mammillary body neurons than healthy mice. Further, the lateral neurons became more hyperactive as the mice aged and were also more susceptible to neurodegeneration than the medial neurons.
To reverse the memory impairments caused by hyperactivity and neurodegeneration in mammillary body neurons, the researchers treated the mice with levetiracetam, a drug used to treat epileptic seizures and has been used in clinical trials for cortical hyperexcitability in Alzheimer’s patients. The treatment was observed to significantly improve the mice’s performance on subsequent memory tasks.
With single-cell RNA sequencing, the researchers identified two major populations of neurons in the mammillary body region: one in the medial mammillary body and the other in the lateral mammillary body. In the lateral neurons, genes related to synaptic activity were very highly expressed, and the researchers also found that these neurons had higher spiking rates than medial mammillary body neurons. Based on those differences, the researchers suspected lateral neurons might be more susceptible to Alzheimer’s.
The researchers also studied human brain tissue from people with and without Alzheimer’s disease and found that the signatures of hyperactivity and neurodegeneration in lateral mammillary bodies were similar to those observed in the mouse studies. These findings suggest that the mammillary body could make a good target for potential drugs that could slow down the progression of Alzheimer’s disease.
The team’s findings aim to help identify specific molecular properties of neuronal classes predisposed to dysfunction and degeneration, potentially leading to the development of new therapeutics that target vulnerable populations and potentially delay the onset of cognitive decline.