Microglia are innate immune cells resident in the brain, analogous in function and behavior to macrophages found elsewhere in the body. They are responsible for clearing debris, aiding in regeneration, destroying pathogens and problem cells, and additionally appear to be involved in maintaining and changing the networks of connections between neurons. An aging brain is characterized by increasing numbers of inflammatory, reactive microglia, representative of the shift to constant inflammatory signaling that takes place throughout the body with advancing age. It is a maladaptive reaction to growing levels of molecular damage, from protein aggregates to mislocalized mitochondrial DNA to the signaling of senescent cells.
Inflammatory microglia are implicated in the development and progression of neurodegenerative conditions. Clearance of microglia, allowing a fresh population to emerge from progenitor cells, appears to improve matters in animal studies of neurodegenerative conditions. Beyond pointing to inflammatory signaling, what exactly are problem microglia doing to provoke neurodegeneration, however? In today's research materials, scientists report the identification of one subset of harmful microglia that are characterized by an active integrated stress response (ISR), leading to secretion of toxic lipids that harm surrounding neurons. In this context, it is worth noting that past animal studies of therapies targeting the ISR have produced interesting results in the context of neurodegeneration.
New Research Identifies Key Cellular Mechanism Driving Alzheimer's Disease
Microglia, often dubbed the brain's first responders, are now recognized as a significant causal cell type in Alzheimer's pathology. However, these cells play a double-edged role: some protect brain health, while others worsen neurodegeneration. Understanding the functional differences between these microglial populations has been a research focus. Researchers have now discovered that activation of a stress pathway known as the integrated stress response (ISR) prompts microglia to produce and release toxic lipids. These lipids damage neurons and oligodendrocyte progenitor cells - two cell types essential for brain function and most impacted in Alzheimer's disease. Blocking this stress response or the lipid synthesis pathway reversed symptoms of Alzheimer's disease in preclinical models.
A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion
The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes. Autonomous activation of ISR in microglia is sufficient to induce early features of the ultrastructurally distinct "dark microglia" linked to pathological synapse loss. In AD models, microglial ISR activation exacerbates neurodegenerative pathologies and synapse loss while its inhibition ameliorates them. Mechanistically, we present evidence that ISR activation promotes the secretion of toxic lipids by microglia, impairing neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR or lipid synthesis mitigates synapse loss in AD models. Our results demonstrate that microglial ISR activation represents a neurodegenerative phenotype, which may be sustained, at least in part, by the secretion of toxic lipids.
View the full article at FightAging
