Protein deposits cause neuron death in Alzheimer’s

A common sign of Alzheimer’s is the build-up in the brain of both tau and amyloid-beta proteins.

A fluorescence  microscopy image of brain tissue from a mouse model of Alzheimer’s showing tau tangles (red), amyloid plaques (white), RNA (green), and cell nuclei (blue). 

A common sign of Alzheimer’s disease is the excessive build-up of two types of protein in the brain: tangles of tau proteins that accumulate inside cells and amyloid-beta proteins that form plaques outside cells. It is not known how these protein deposits are related to the death of neurons in the brain, the major hallmark of the disease. A study by scientists at the Broad Institute of MIT and Harvard provides some answers. The work was published recently in Nature Neuroscience.

The team used a new method it developed in a mouse model to reveal how brain cells located near these proteins change as the disease progresses. The technique, called STARmap PLUS, is the first to simultaneously map gene expression of individual cells and their location, and the spatial distribution of specific proteins in intact tissue samples.

The researchers studied brain tissue from the Alzheimer’s mouse model at two different stages of the disease at high spatial resolution. In the earlier stage, they observed a central core of amyloid plaque surrounded by a type of immune cell in the brain called microglia, which are known to play a role in the disease. The microglia closer to the plaques showed genetic signatures linked to neurodegeneration.

This core-shell structure and differences in gene expression of cells surrounding the proteins give scientists a clearer picture of how cells respond to the protein deposits. Scientists believe that these insights could help them evaluate current treatments for Alzheimer’s and develop new ones.

“From these kinds of studies, you can infer what’s going on in a far more detailed way than you could if you just looked at cells from dispersed tissue samples that don’t have their spatial context any more,” said Morgan Sheng, co-senior author of the study and a professor of neuroscience at MIT. The team used different molecular techniques to do in situ sequencing and imaging to create a 3-D map of the tagged proteins and the expression of more than 2,700 genes. The scientists found that the brain’s inflammatory response and the differentiation of glial cells, such as the microglia, were connected to disease progression.

Although other researchers had previously observed a core-shell structure around plaque, the new gene expression data revealed that the microglia were more “activated” to trigger an inflammatory response closer to the plaque. Understanding when, where, and how microglia activate could be an important part of deciphering their role in the disease.

A key advantage of STARmap PLUS, Xiao Wang, a co-senior author on the study and a professor of chemistry at MIT, said is that it collects both protein and gene expression information from a single sample, making it easier to align and compare different kinds of data at high resolution. It can also detect features smaller than cells, which helps distinguish individual cells even when they are densely crowded together in the brain. The researchers say that a crucial next step will be to use the approach to study Alzheimer’s progression in human brain tissue samples.