Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PC, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, Hansen DV. Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models. Cell Rep. 2018 Jan 16;22(3):832-847. PubMed.
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Saba University School of Medicine
This study is a tour de force that provides significant insight into the complexity of gene expression profiles of AD and related mouse models, with a particular focus on microglial cells.
Several large studies have been performed recently analyzing gene expression changes in neurodegenerating brains, and almost all suffer from the same caveat. I will try to illustrate the problem with an example.
Imagine scientists interested in knowing the number of testicles per person in a human population. They are likely to conclude that statistically, on average, humans have one testicle per person. Although by itself a sound conclusion, from a biological point of view it is a silly one. We all know that males have two while females have none. Now if due to a disaster, the number of males in a population were to be reduced by half, these scientists could conclude that, based on total population data, the average number of testicles would fall to two-thirds per person. Obviously, on a per person level, still every man would have two and every woman would have none!
A similar problem exists in gene expression analyses performed on degenerating brains. In such a brain, there are some regions with up to 70 percent loss of neurons. Some past studies have concluded that in AD brains, APP gene expression levels are similar or lower compared to those of healthy brains. Far-reaching conclusions are formulated from such results in the context of production and clearance of APP and its derived peptides.
Such conclusions, however, are likely to be as silly as the two-thirds testicle per person conclusion. If just 30 percent of neurons show a somewhat decreased APP mRNA level, this probably indicates that on a per neuron level APP levels have been significantly increased in many different neuron types in such a brain. Also, other conclusions, like the level of gliosis and inflammation observed in AD brains, are likely to be significantly exaggerated when taking into account that some of the brain regions analyzed have lost a significant number of neurons.
No wonder little overlap is found between mouse models of AD and human AD. The mouse models do not show the significant amount of neuronal cell death and the gene expression patterns are significantly different.
Too many of the neurodegeneration-related changes in expression profiles from whole tissue samples are the result of altered cell-type composition and not due to transcriptional regulation of the genes involved. The field of neurodegeneration research has to make a significant effort to find experimental setup or analysis methods that capture gene expression in brains on a per cell type basis. The "whole tissue homogenate" approach produces too many misleading and erroneous results. Not really knowing if APP is under- or overexpressed in neurons of degenerating brains, or if microglia genes are overexpressed or downregulated on a per cell basis, is not acceptable anymore. A cell-type level of analysis should become the norm as soon as possible.
As a field, scientists need to come together and find some kind of consensus on how to deal with the cell type heterogeneity of the degenerating brain.
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