How brain neural circuit dysfunction, pathological insults, and the demise of neurons drive memory deficits in Alzheimer’s disease (AD) are not fully understood. One of the first brain regions to show neurodegeneration in AD is a part of the hypothalamus called the mammillary body. Now, MIT neuroscientists have identified neurons in the mammillary body that may contribute to some of the earliest symptoms of AD.

The findings are published in the journal Science Translational Medicine in an article titled, “Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer’s disease.”

“The neural circuits governing the induction and progression of neurodegeneration and memory impairment in AD are incompletely understood, the researchers wrote. “The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD is unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons.”

“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,” said Li-Huei Tsai, PhD, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study.

“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,” said Mitchell Murdock, a graduate student in the department of brain and cognitive sciences at MIT and one of the lead authors of the paper. “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 2019 study using a mouse model of AD, Tsai, former MIT postdoc Wen-Chin (Brian) Huang, PhD, and others found that the mammillary bodies—a pair of structures found on the left and right underside of the hypothalamus—had the highest density of amyloid beta.

The researchers used single-cell RNA-sequencing to learn more about the mammillary body’s function. They identified two major populations of neurons: 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.

They studied a mouse model with five genetic mutations linked to early-onset Alzheimer’s in humans. The researchers found that these mice showed more hyperactivity in lateral mammillary body neurons than healthy mice. However, the medial mammillary body neurons in healthy mice and the Alzheimer’s model did not show any such differences.

The researchers found that this hyperactivity emerged around two months of age (the equivalent of a young human adult) before amyloid plaques begin to develop.

“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 said.

The Alzheimer’s mouse model showed impairments in forming new memories, but when the researchers treated the mice with a drug known as levetiracetam, which is now used to treat epilepsy, neuronal hyperactivity was reduced.

The researchers also studied human brain tissue from the Religious Orders Study/Memory and Aging Project (ROSMAP), a longitudinal study that has tracked memory, motor, and other age-related issues in older people since 1994.

Similar to the mouse studies, the researchers also found signatures of hyperactivity in the lateral mammillary bodies from Alzheimer’s tissue samples, including overexpression of genes that encode potassium and sodium channels.

Their findings suggest that the mammillary body could make a good target for potential drugs that could slow down the progression of AD, the researchers say.

The team is now working on further defining how the lateral neurons of the mammillary body are connected to other parts of the brain, to figure out how it forms memory circuits. The researchers also hope to learn more about what properties of the lateral neurons of the mammillary body make them more vulnerable to neurodegeneration and amyloid deposition.

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