Fight Aging!

Researchers here report on a drug discovery effort targeting PU.1, a gene implicated in increased inflammation of microglia in the brain. Microglia are innate immune cells of the central nervous system. Like macrophages in the rest of the body, they react to the damage and dysfunction of aging with increased inflammatory behavior, a maladaptive response that worsens pathology. Chronic, unresolved inflammation is clearly disruptive to tissue function wherever it occurs in the body. In the brain, chronic inflammation is a well-studied feature of conditions such as Alzheimer's disease. A greater population of inflammatory microglia is characteristic of aging and neurodegenerative conditions, and the research community is increasingly interested in finding ways to address this issue.

A 2015 study implicated PU.1 as a regulator of errant microglia inflammation in a mouse model of Alzheimer's disease. Genetically knocking down PU.1 in the body is not a viable therapeutic strategy given its importance in normal healthy function. Researchers therefore screened more than 58,000 small molecules from libraries of FDA-approved drugs and novel chemicals to see if any could safely and significantly reduce key inflammation and Alzheimer's related genes regulated by by PU.1 in cell cultures. After several rounds of increasingly stringent screening, they narrowed the field down to six chemicals. A11 was by far the most potent among them.

Researchers tested the effects of A11 doses on the function of human microglia-like cells cultured from patient stem cells. When they exposed the microglia-like cells to immune molecules that typically trigger inflammation, cells dosed with A11 exhibited reduced expression and secretion of inflammatory cytokines and less of the cell body shape changes associated with microglia inflammatory responses. The cells also showed less accumulation of lipid molecules, another sign of inflammatory activation. Looking at gene expression patterns, the scientists observed that A11-treated cells exposed to inflammatory triggers behaved much like unperturbed microglia, suggesting that A11 helps prevent microglia from overreacting to inflammatory cues.

In a new paper, researchers started with experiments to further validate that PU.1 would be a therapeutically meaningful target. To do that the scientists compared gene expression in immune cells of postmortem brain samples from Alzheimer's patients and mouse models and matching non-Alzheimer's controls. The comparisons showed that Alzheimer's effects major changes in microglial gene expression and that an increase in PU.1 binding to inflammatory gene targets was a significant component of that change. Moreover, they showed that reducing PU.1 activity in a mouse model of Alzheimer's reduced inflammation and neurodegeneration, the death of neurons.

Two more lab tests aimed at understanding how A11 exerts its effects revealed that it doesn't change PU.1 levels. Instead it counteracts PU.1 activity by recruiting several proteins including MECP2, HDAC1, SIN3A and DMNT3A, known to repress expression of its targets. Essentially amid Alzheimer's disease, A11 tamps down what PU.1 amps up.

Link: https://picower.mit.edu/news/molecule-reduces-inflammation-alzheimers-models