Why does cognition falter with age? In the January 20 Nature, researchers led by Katrin Andreasson at Stanford University, Palo Alto, California, lay the blame on malfunctioning myeloid cells. The authors found that as these cells age, they begin to hoard glucose rather than burn it, precipitating an energy crisis. The starving cells then pump out pro-inflammatory factors. These harmful immune cell changes are driven by the circulating prostaglandin E2 (PGE2), which rises with age. When the authors inhibited a PGE2 receptor in macrophages and microglia of aging mice, the myeloid cells maintained a youthful state, with vigorous energy production and little inflammation. Importantly, the treatment prevented age-related cognitive decline. Old mice with dampened PGE2 signaling kept the synaptic plasticity and memory skills of young animals.
- In aging mice, myeloid cells face an energy crisis.
- As they release inflammatory factors, synapses and cognition suffer.
- Blocking a prostaglandin receptor rescued their metabolism, as well as synapses and memory.
“Myeloid cells are central to age-associated inflammation,” Andreasson told Alzforum. She believes this process affects peripheral organs too, and could suggest therapeutic targets for preventing numerous age-related conditions, including Alzheimer’s disease.
Others were enthusiastic. “This is a breakthrough paper that sets the stage for new findings,” said Costantino Iadecola at Weill Cornell Medical College, New York. Michal Schwartz and Tommaso Croese at Weizmann Institute of Science, Rehovot, Israel, noted that broad-spectrum anti-inflammatory drugs such as NSAIDs have not helped treat AD, despite a wealth of evidence that immune cells affect the brain. “Rather than inhibiting immune-cell function, approaches that renew their ability to maintain and repair tissue homeostasis, such as the one used here, are expected to prove effective in counteracting neurodegeneration,” they wrote to Alzforum (full comment below).
NSAIDs block the enzyme cyclooxygenase 2 (COX-2) that promotes inflammation. Although epidemiological data link NSAID use to a lower risk of dementia, treatment trials have found no benefit (Nov 2001 news; Apr 2019 news). One problem may be that COX-2 has beneficial as well as harmful effects.
Andreasson focused instead on PGE2, which lies downstream of COX-2. This hormone-like lipid messenger signals through four G-protein-coupled receptors (see image at right). In a previous study, the authors had found that conditionally deleting one of these receptors, EP2, in myeloid cells of APP/PS1 mice boosted microglial function and Aβ clearance, while suppressing harmful inflammation and preserving synaptic function and memory (Johansson et al., 2015). Because EP2 rises with age, Andreasson wondered if the same inflammatory pathway might also be responsible for harmful changes during aging.
First author Paras Minhas initially tested this in human cells, isolating monocytes from blood donated by healthy people who were either under 35 or over 65. After differentiating these cells into macrophages, the authors confirmed that cells from older people made twice as much PGE2 and EP2 as did cells from the younger group. What effect might this have? Adding exogenous PGE2 to cultured macrophages suppressed both cellular respiration and glycolysis, the two pathways for generating energy. Instead of burning glucose, the cells stored it in the form of glycogen. Likely, this is because EP2 signaling turns on glycogen synthase. Adding an EP2 inhibitor to the cultured cells, on the other hand, boosted both types of energy production.
Not only did aging cells struggle to burn glucose, they also failed to make use of alternative sources of fuel for respiration. Cells from young donors were better able to use lactate and pyruvate. This limitation makes old macrophages more dependent than young ones on a functioning glycolytic pathway, the authors noted.
What are the consequences in vivo? The authors conditionally deleted EP2 in the myeloid cells of transgenic mice, which halved levels of the receptor. Macrophages from 20-month-old EP2-deficient mice maintained normal cellular respiration and glycolysis. In age-matched control animals, macrophage function degraded with age. The cells secreted pro-inflammatory factors, phagocytosed poorly, and had fewer and malformed mitochondria. EP2-deficient macrophages, on the other hand, had none of these problems, behaving like those from young mice.
It is unclear how impaired glycolysis or respiration promotes inflammation, but the authors noted that suppression of the electron transport chain boosts levels of the intermediate succinate, which is known to activate pro-inflammatory cytokines (Tannahill et al., 2013; Lampropoulou et al., 2016; Mills et al., 2016). In future work, Andreasson plans to dig deeper into the mechanism.
Notably, these immune cell changes affected the brain. Old control mice have impaired synaptic plasticity and memory compared to young animals, but the 20-month-old knockouts remembered the previous location of an object and escaped from a circular platform as well as did young animals. Hippocampal slices from the knockouts mounted stronger long-term potentiation, and made twice as much of key synaptic proteins such as synapsin and PSD95 in the hippocampus compared to age-matched controls.
Treating aged wild-type mice for one month with pharmacological EP2 inhibitors produced similar benefits. Treated animals had better microglial energy metabolism, synaptic plasticity, and memory. Intriguingly, mice reaped these cognitive benefits even when treated with an inhibitor that does not cross the blood-brain barrier. This hints that peripheral macrophages, or blood-borne factors they produce, could be responsible.
Bruno Imbimbo of Chiesi Pharmaceuticals in Parma, Italy, believes the finding has therapeutic potential. “The hope is that selective EP2 antagonists would work much better than COX-2 inhibitors, which indiscriminately block all four PGE2 receptors,” he wrote to Alzforum (full comment below).
Several companies make selective EP2 antagonists, but none are approved for human use. Pfizer’s PF-04418948 was tested for safety in a Phase 1 study in 2010, but the company halted clinical development. Researchers at Emory University are developing several selective EP2 inhibitors, which they are investigating for cancer therapy because EP2 signaling aids tumor cell survival and migration (Ganesh, 2014; Hou et al., 2020).
Iadecola noted that targeting EP2 could be complicated. The receptor is known to regulate blood flow and pressure, and has been found to protect the brain during strokes (Wu et al., 2017). However, other studies implicate EP2 in ischemic damage (Luo et al., 2017; Liu et al., 2019; Li et al., 2020). Altogether, the data suggest EP2 would have to be carefully modulated for therapeutic benefit.
Iadecola suggested looking downstream instead. He wondered if the EP2 pathway might exert some of its harmful effects in aging macrophages via the production of free radicals. Blocking mitochondrial respiration is known to produce free radicals in some cells, and these have been implicated in many aging-related conditions. “The relative contribution of free radicals versus metabolic dysfunction should be addressed in future work,” Iadecola said.—Madolyn Bowman Rogers
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