The Cellular-Molecular Landscape of the Alzheimer`s Brain

Alzheimer’s disease (AD) is one of the most pressing global medical issues to date. A better understanding of the cellular circuits and molecular mechanism driving disease initiation and progression, will enable the discovery of new and efficient therapeutic strategies. The enormous cellular diversity in the brain is challenging the research in the field, however, the emergence of single nucleus RNA-seq (sNuc-Seq) methods, provide a unique opportunity to study cellular circuits and molecular mechanisms in complex tissues with single cell resolution and high-throughput. We have previously shown that sNuc-Seq enables sensitive, efficient, and unbiased classification of cell types and dynamic cell states. Here, we used sNuc-Seq to profile hundreds of thousands of nuclei of wild-type and AD mouse-models along different ages, as well as post mortem brains of aging individuals ranging between healthy and advanced AD. We find altered cellular frequencies, cell states and molecular pathways in AD brains, revealing multiple cell types, predominantly glia cells, potentially involved in disease progression. Interestingly, we find a novel disease associated astrocytes (DAAs), that stem from a switch in a homeostatic population of astrocytes. The DAAs are up-regulating expression of inflammatory genes and of response genes to reactive oxygen species and DNA damage. Overall, we are paving the way for a systemic charting of the unique cellular and molecular landscape of the Alzheimer’s brain, which will advance our understanding of cellular-molecular disease mechanisms.