Neuroscientists have successfully identified the first brain cells that show the signs of neurodegeneration in Alzheimer’s disease.

A crucial characteristic of Alzheimer’s disease is neurodegeneration, which is the gradual deterioration of neuron function. Yet, it does not act in the same way on various areas of the brain.

MIT researchers have recently uncovered that a section of the hypothalamus known as the mammillary body is among the first to exhibit neurodegeneration in Alzheimer’s disease. Within this region, they identified a specific group of neurons that are particularly susceptible to neurodegeneration and hyperactivity. Moreover, they found that this damage results in memory impairments.

The researchers propose that this particular region might play a significant role in the initial manifestations of Alzheimer’s disease, highlighting it as a promising candidate for the development of new therapeutic drugs to combat the illness.

“It is fascinating that only the lateral mammillary body neurons, not those in the medial mammillary body, become hyperactive and undergo neurodegeneration in Alzheimer’s disease,” comments senior author Li-Huei Tsai.

Using a medication that is already used to treat epilepsy, the researchers demonstrated in a trial of mice that they could repair memory deficits brought on by hyperactivity and neurodegeneration in mammillary body neurons.

The paper’s principal authors are former MIT postdoc Wen-Chin (Brian) Huang, MIT graduate students Zhuyu (Verna) Peng, and Mitchell Murdock. It was published in Science Translational Medicine today.

Inherent Susceptibility to Degeneration

As Alzheimer’s disease advances, neurodegeneration transpires concurrently with the accumulation of amyloid beta plaques and misshapen Tau proteins, which create tangled formations in the brain. A lingering question in the field is whether neurodegeneration occurs randomly, or if specific neuron types are more vulnerable to its effects.

“If we could identify specific molecular properties of classes of neurons that are predisposed to dysfunction and degeneration, then we would have a better understanding of neurodegeneration,” Murdock adds. “This is clinically important because we could find ways to therapeutically target these vulnerable populations and potentially delay the onset of cognitive decline.”

In a study conducted in 2019, researchers Tsai and Huang investigated the link between Alzheimer’s disease and the mammillary bodies in mice. These structures, located on the underside of the hypothalamus, were found to have the highest concentration of amyloid beta. While the mammillary bodies are known to play a role in memory, their exact function in normal memory and Alzheimer’s disease has yet to be fully understood.

In order to gain further insight into the mammillary bodies’ function, the researchers utilized single-cell RNA-sequencing to identify active genes within different types of cells in a tissue sample. Through this technique, they discovered two distinct populations of neurons: one in the medial mammillary body and another in the lateral mammillary body. The lateral neurons exhibited highly expressed genes related to synaptic activity and higher spiking rates compared to the medial mammillary body neurons.

Researchers speculated, based on these differences, that lateral neurons might be more susceptible to Alzheimer’s disease. They looked at a mouse model with five genetic variants associated with human early-onset Alzheimer’s disease to answer that issue. They discovered that compared to healthy mice, these animals had much higher lateral mamillary body neuron hyperactivity. Nevertheless, there were no such alterations in the medial mammillary body neurons of healthy mice and those in the Alzheimer’s model.

The researchers discovered that this excitability arose at a very young age — around two months (the equivalent of a young human adult), before the formation of amyloid plaques. As the mice grew older, the lateral neurons were even more excitable, and they were also more vulnerable to neurodegeneration than the medial neurons.

“We think the hyperactivity is related to dysfunction in memory circuits and is also related to a cellular progression that might lead to neuronal death,” Murdock adds.

The Alzheimer’s mouse model exhibited difficulties in forming new memories; however, when the rodents were administered a substance that reduces neuronal excitability, their performance on memory tasks was significantly enhanced. Levetiracetam is a medication used for the treatment of epileptic seizures; it is also now being tested in clinical studies for the management of epileptiform activity, or increased epileptic susceptibility due to hyperexcitability in the cerebral cortex.

Human-mouse comparison

The Religious Orders Study/Memory and Aging Project (ROSMAP), a longitudinal study that has followed memory, motor, and other age-related disorders in senior citizens since 1994, was also used to analyze human brain tissue. Single-cell RNA-sequencing of human mammillary body tissue revealed two clusters of neurons, one corresponding to the lateral mammillary body neurons and the other to the medial mammillary body neurons, much as was previously shown in mice.

In Alzheimer’s tissue samples, the researchers also found signs of hyperactivity in the lateral mammillary bodies, such as the overexpression of genes that code for potassium and sodium channels. This was similar to what they found in the mouse studies. They also discovered that the lateral neuron cluster had more neurodegeneration than the medial cluster in those samples.

In other studies of Alzheimer’s patients, plaques and changes in the structure of synapses were found early on in the disease, along with a loss of volume in the mammillary body. According to the researchers, all of these data point to the mamillary body as a possible pharmacological target that might potentially halt the course of Alzheimer’s disease.

Tsai’s team is now trying to determine how the mammillary body’s lateral neurons communicate with other brain regions to construct memory circuits. The study’s secondary objective is to elucidate the mechanisms through which mammillary body lateral neurons are uniquely susceptible to neurodegeneration and amyloid deposition.

Source: 10.1126/scitranslmed.abq1019

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