A new study by researchers in The Picower Institute for Learning and Memory at MIT provides evidence from both mouse models and postmortem human tissue of a direct link between two problems that emerge in Alzheimer’s disease: a buildup of double-stranded breaks (DSBs) in the DNA of neurons and the inflammatory behavior of microglia, the brain’s immune cells.
A key new finding is that neurons actively trigger an inflammatory response to their genomic damage. Neurons have not been known to signal the brain’s immune system in Alzheimer’s disease, said study lead author Gwyneth Welch, a former MIT Brain and Cognitive Sciences graduate student in the lab of senior author Li-Huei Tsai.
“This is a novel concept in neuroscience: the idea that neurons can be activating inflammatory activity in response to DNA damage,” Welch said. “The general idea was that neurons have a more passive relationship with microglia regarding age-associated neuroinflammation.”
Instead, what Welch, Tsai and co-authors report in Science Advances is that neurons coping with mounting DSBs go through stages of first trying to fix their fractured DNA and then, when it apparently fails, sending out via molecular signals to microglia, which responded by taking on a more inflammatory state. In experiments where the scientists interrupted the immune signaling, they prevented microglia from entering that state and degrading neural circuit connections, or synapses.
Members of Tsai’s lab have been studying DSBs in the context of Alzheimer’s for more than a decade. Tsai said the new findings add to the emerging understanding of the role they play in Alzheimer’s.
“We have a longstanding interest in understanding DNA breaks in neurons,” said Tsai, Picower Professor of Neuroscience and a founder of MIT’s Aging Brain Initiative. “We previously showed that DNA double stranded breaks are necessary for the induction of activity-regulated gene expression in neurons but we also observed profound DNA damage in neurons in the early stages of neurodegeneration.
Source: Read Full Article