For the first time, researchers have analysed gene expression patterns of individual cells of patients with Alzheimer’s disease. In an early release of the study, published on 1 May in Nature, scientists have revealed the distinct cellular pathways affected by the disease (1).
Tracing the disease down to a single cell type
The team of researchers at the Massachusetts Institute of Technology (MIT) used something called single-cell analysis to sequence the RNA of cells isolated from brain samples of Alzheimer’s patients.
All the samples were part of the Religious Orders Study, a longitudinal clinical-pathologic cohort study of ageing and Alzheimer’s disease. Samples were obtained after the patients with varying degrees of the disease after they had died.
More specifically, the cells came from 24 patients with severe Alzheimer’s as well as 24 patients of a similar age without the disease – in total, more than 80,000 so-called single-nucleus transcriptomes.
The most interesting part of the study is that single-cell technologies enabled scientists analysed RNA from single cells of a known cells type. Whereas, previous studies only examined a mix of cells taken from diseased versus healthy brain tissues.
But by isolating individual cells, it’s now possible to see differences in gene expression among the various cell types of the brain, allowing researchers to pinpoint which cell types are involved in the disease. Only the most abundant cell types could be analysed, mainly excitatory and inhibitory neurons, and also some non-neuronal brain cells such as oligodendrocytes, astrocytes, and microglia.
The scientists found that the progression of the disease seems to be highly cell-specific but mostly during the early stages. In other words, cell types showed different gene expression patterns in Alzheimer’s patients.
Cell-specific changes occur early in the disease
The most significant changes in gene expression were related to axons, long nerve cells that transmit electrical impulses throughout the nervous system, and is therefore important for cellular communication. In particular, changes in the genes that influence axon regeneration and myelination ― a fatty substance surrounding axons that speed up the transmission of electrical impulses.
In the later stages of the disease, changes gene expression were more uniformly across all the cell types, mostly related to the stress response and programmed cell death.
Gender differences in Alzheimer’s
One surprising finding was that cells from female patients with Alzheimer’s showed more dramatic changes in gene expression than cells from males; despite similar symptoms, including amyloid plaques and cognitive impairment. This was particularly evident in oligodendrocytes, the cells that produce myelin.
Previous MRI studies revealed that female patients with severe memory deficits had much more damage to the white matter of the brain than male subjects. The scientists are not sure why this may be the case. Further studies are needed and may have implications on treatment approaches for male versus female patients.
Setting the stage for further research
According to the authors, the single-cell analysis provides the first “blueprint” for further investigations on the “molecular underpinnings and cellular basis” of Alzheimer’s disease. The findings could offer potential new drug targets for combating the devastating disease which afflicts more than 35 million people worldwide.
(1) Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature (2019). DOI: 10.1038/s41586-019-1195-2