‘Brain mechanisms of microRNA-132 decoded’ – Written by Charlotte Harrison, Science Writer.
The microRNA miR-132 likely plays a role in Alzheimer’s disease; the molecule is downregulated in the brain of Alzheimer’s disease patients and in mouse models. Increasing miR-132 levels in the Alzheimer’s mouse brain stops amyloid and tau pathologies, and improves neuronal function and memory.
But how miR-132 produces these effects is unknown. Now, with the aim of edging miR-132 towards clinical translation, a new study has combined miR-132 loss- and gain-of-function approaches, single-cell transcriptomics, proteomics and other datasets to identify the molecular pathways that are targeted by miR-132 in mouse hippocampus.
Shifting microglial states
First, the researchers showed that miR-132 overexpression or knockdown did not lead to transcriptional alterations in either astrocytes or neurons. However, miR-132 modulation caused transcriptional responses in microglia – the immune cells of the brain.
Specifically, miR-132 overexpression reduced the proportion of disease-associated microglia; these cells are a subpopulation of microglia that might play a protective role in neurodegeneration. Conversely, miR-132 depletion increased this microglial fraction.
Ultimately, using human microglial cultures derived from induced pluripotent stem cells (iPSC), the authors found that miR-132 has a regulatory role, shifting microglia from a disease-associated state to a homeostatic state.
Moreover, the levels of apoptosis-related genes in iPSC-derived microglial cultures suggested that the effects of miR-132 on microglial activation and homeostasis might be partly mediated through the regulation of apoptosis.
A link to Alzheimer’s disease
“We know that microRNA-132 performs various functions in neurons, but surprisingly, we found that this microRNA also plays a role in microglia. This is interesting in the case of Alzheimer’s disease because we believe that neuroinflammation plays a significant role [in the pathogenesis],” said the authors in a press release.
But whether the change from the disease-associated microglial state to the homeostatic state is beneficial or detrimental needs further study. The authors note that disease-associated microglia may initially aid cell clearance during the early stages of Alzheimer’s disease but later lead to the death of healthy cells. The authors plan to examine the effect of increasing microRNA-132 in neurons and microglia in a mouse model of Alzheimer’s disease.