A breakdown in communication between neurons and the brain’s resident “cleaner” cells is closely intertwined with the progression of Alzheimer’s disease, according to a new study of tissue from human brain donors. The new analysis unweaves the complicated mesh of signaling pathways and cell-to-cell networks that go awry in this neurodegenerative disorder and could facilitate future research into new therapeutic targets. In the healthy brain, neurons and non-neuronal cells constantly communicate with each other to gather information, maintain homeostasis, and prune and clean the nervous system. Recent research has shown that these delicate lines of cross-talk break down in neurodegenerative diseases such as Alzheimer’s disease, suggesting that cell-to-cell communication could be a target for new drugs. In this study, Ricardo D’Oliveira Albanus and colleagues examined transcriptional data from 67 brain donors, including patients with different subtypes of Alzheimer’s disease, and searched for disruptions in cross-talk between different types of neuronal cells. Their experiments revealed a gene network that controls communication between neurons and microglia – supportive cells that help clean up the nervous system – by acting through the proteins TREM2 and SEMA6D. Using spatially resolved gene expression analysis and tissue staining techniques, D’Oliveira Albanus et al. observed that this gene network activated near plaques of disease-linked amyloid-beta and microglia that express TREM2. However, the expression of TREM2 and SEMA6D declined during the later stages of Alzheimer’s disease, suggesting that loss of communication with neurons prevents microglia from properly clearing out harmful amyloid-beta plaques. The team then studied gene-edited microglia derived from stem cells in culture and confirmed that the cells depend on TREM2 and SEMA6D to engulf amyloid-beta plaques. “We demonstrate that characterizing cellular cross-talk networks can yield insights into [Alzheimer’s disease] biology […] and find previously unknown therapeutic targets and pathways,” the authors write.
