Myeloid Metabolic Crisis May Trigger Cognitive Decline in Aging Brain

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).

Turn the PaGE. NSAID effects are too broad to be helpful, since COX-1 and COX-2 affect numerous processes. In mouse myeloid cells, inhibiting EP2, a specific downstream receptor of PGE2, prevented age-related cognitive decline. [Courtesy of Minhas et al., Nature.]

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

Comments

  1. For decades, cognitive deterioration occurring during aging was considered to be neuronal-centric, and thus was attributed solely to neuron exhaustion, dysfunction, or, in the extreme case, to neuronal loss. Over the last two decades, emerging studies described additional aging-related dysfunctions in non-neuronal populations, mainly in the brain-resident myeloid cells, the microglia, which affect brain function. In addition, we now know that cognitive performance is also a reflection of the integrity of the peripheral immune system (Kipnis et al., 2004; Ziv et al., 2006; Derecki et al., 2010; Filiano et al., 2016), and thus, maladaptation of the immune system, which often occurs in chronological aging, has been proposed as an exacerbating factor in brain aging as well (Da Mesquita et al., 2018; Baruch et al., 2014; Wyss-Coray, 2016). 

    In this paper, Minhas and colleagues elegantly demonstrate the relevance of metabolic activity for myeloid cells’ fate and function, and describe the implications of myeloid cell metabolic dysfunction for cognitive performance of mice.

    They first show that the expression of the EP2 receptor, one of the four Prostaglandin receptors, is markedly increased in human monocyte-derived macrophages (MDM) of aged individuals (>65 years old) and is associated with decreased glycolysis and with mitochondrial abnormalities. Knockdown of the EP2 receptor in myeloid cells prevents cognitive aging of mice, and shifts MDM polarization to a more tissue-repairing state, characterized by the increased expression of scavenger receptors such as CD206 and CD163, while decreasing co-stimulatory signals such as CD86.

    Considering that microglial cells are the main myeloid population in the brain, the authors tested the effect of EP2 inhibition using both brain-penetrant and brain-impermeable EP2 antagonists. Brain-penetrant EP2 inhibitors improved glycogen synthesis, enhanced the glycolytic response and TCA cycle of myeloid cells (both microglia and peripheral macrophages), and improved cognitive performance. Even more importantly, in the final part of their study, the authors found that blocking EP2 in the periphery was sufficient to reverse cognitive loss. This observation is in line with several recent studies showing that manipulating the peripheral immune system is effective in modifying neurodegenerative diseases, including dementia and Alzheimer’s disease, that are characterized by cognitive impairment, and that in all of them, a key role is played by the circulating myeloid cells (Rosenzweig et al., 2019; He et al., 2020; Xing et al., 2021; Yang et al., 2020; Chiot et al., 2020). 

    This study joins the large body of evidence supporting the current view that the fate of the immune system affects brain functions, and that targeting the immune system may be a powerful tool to treat age-related cognitive disorders. We learned from previous clinical trials that targeting systemic inflammation with broad-spectrum anti-inflammatory drugs was not effective in treating Alzheimer’s disease. Thus, 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.

    References:

    Kipnis J, Avidan H, Caspi RR, Schwartz M. Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia. Proc Natl Acad Sci U S A. 2004 Oct 5;101 Suppl 2:14663-9. PubMed.

    Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006 Feb;9(2):268-75. PubMed.

    Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2010 May 10;207(5):1067-80. Epub 2010 May 3 PubMed.

    Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, Peerzade SN, Chen H, Lee KS, Scott MM, Beenhakker MP, Litvak V, Kipnis J. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016 Jul 21;535(7612):425-9. Epub 2016 Jul 13 PubMed.

    Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191. Epub 2018 Jul 25 PubMed.

    Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, Berkutzki T, Barnett-Itzhaki Z, Bezalel D, Wyss-Coray T, Amit I, Schwartz M. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014 Aug 21; PubMed.

    Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature. 2016 Nov 10;539(7628):180-186. PubMed.

    Rosenzweig N, Dvir-Szternfeld R, Tsitsou-Kampeli A, Keren-Shaul H, Ben-Yehuda H, Weill-Raynal P, Cahalon L, Kertser A, Baruch K, Amit I, Weiner A, Schwartz M. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

    He Z, Yang Y, Xing Z, Zuo Z, Wang R, Gu H, Qi F, Yao Z. Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice. Cell Death Dis. 2020 Jun 8;11(6):440. PubMed.

    Xing Z, Zuo Z, Hu D, Zheng X, Wang X, Yuan L, Zhou L, Qi F, Yao Z. Influenza vaccine combined with moderate-dose PD1 blockade reduces amyloid-β accumulation and improves cognition in APP/PS1 mice. Brain Behav Immun. 2021 Jan;91:128-141. Epub 2020 Sep 19 PubMed.

    Yang Y, He Z, Xing Z, Zuo Z, Yuan L, Wu Y, Jiang M, Qi F, Yao Z. Influenza vaccination in early Alzheimer's disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells. J Neuroinflammation. 2020 Feb 19;17(1):65. PubMed.

    Chiot A, Zaïdi S, Iltis C, Ribon M, Berriat F, Schiaffino L, Jolly A, de la Grange P, Mallat M, Bohl D, Millecamps S, Seilhean D, Lobsiger CS, Boillée S. Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival. Nat Neurosci. 2020 Nov;23(11):1339-1351. Epub 2020 Oct 19 PubMed.

    View all comments by Tommaso Croese View all comments by Michal Schwartz

  2. The recent work of Minhas and colleagues unveils the crucial role of myeloid prostaglandin EP2 signaling in the bioenergetic dysfunction processes that occur during aging.

    The authors demonstrated that in aged mice, both central and peripheral inhibition of myeloid EP2 signaling attenuated or reversed cellular bioenergetics, systemic, and neuroinflammatory dysfunction. In addition, blockade of peripheral EP2 receptors restored hippocampal synaptic plasticity and spatial memory in aged mice.

    This work opens the possibility of testing selective EP2 antagonists in aging CNS clinical conditions, including Alzheimer’s disease (AD) and other neurodegenerative diseases. We know that prostaglandin E2 (PGE2) is a typical inflammatory mediator released after COX-2 induction in injured tissues and cells, mostly by immune cells such as mast cells, basophils, or macrophages that accumulate in the area of injury.

    In the past, COX-2 inhibitors were tested in patients with mild to moderate AD, in subjects with mild cognitive impairment, and even in cognitively normal subjects at risk of developing AD. Unfortunately, these studies failed to show cognitive or clinical benefit, and in some cases accelerated cognitive decline (Thal et al., 2005). Since PGE2 activates four different receptors (EP1, EP2, EP3, and EP4), the hope is that selective EP2 antagonists would work much better than COX-2 inhibitors, which indiscriminately block all four PGE2 receptors.

    Minhas and colleagues have nicely demonstrated that EP1, EP3, and EP4 receptors are similarly expressed in young and aged human monocyte-derived macrophages (MDMs) and that EP1-, EP3-, and EP4-selective antagonists do not affect basal respiration and glycolysis of human MDMs. However, they did not study EP1-, EP3-, and EP4-selective antagonists in young and aged human MDMs. Most importantly, they did not study these selective antagonists in vivo in aged mice. This information would be very important to demonstrate that only selective EP2 antagonists reverse age-related energetic and cognitive dysfunction in aged mice and provide the link to justify future clinical trials with selective EP2 antagonists, despite the clinical failure of unselective COX-2 antagonists.

    References:

    Thal LJ, Ferris SH, Kirby L, Block GA, Lines CR, Yuen E, Assaid C, Nessly ML, Norman BA, Baranak CC, Reines SA, . A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology. 2005 Jun;30(6):1204-15. PubMed.

    View all comments by Bruno Pietro Imbimbo

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References

News Citations

  1. Large Prospective Study Finds NSAIDs Reduce Risk of Developing AD
  2. Closing the Book on NSAIDs for Alzheimer’s Prevention

Research Models Citations

  1. APPSwe/PSEN1dE9 (C3-3 x S-9)

Paper Citations

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  5. Ganesh T. Prostanoid Receptor EP2 as a Therapeutic Target. J Med Chem. 2014 Jun 12;57(11):4454-65. Epub 2013 Dec 4 PubMed.
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  7. Wu H, Wu T, Han X, Wan J, Jiang C, Chen W, Lu H, Yang Q, Wang J. Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice. J Cereb Blood Flow Metab. 2017 Jan;37(1):39-51. Epub 2016 Jan 8 PubMed.
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External Citations

  1. Phase 1

Further Reading

Primary Papers

  1. Minhas PS, Latif-Hernandez A, McReynolds MR, Durairaj AS, Wang Q, Rubin A, Joshi AU, He JQ, Gauba E, Liu L, Wang C, Linde M, Sugiura Y, Moon PK, Majeti R, Suematsu M, Mochly-Rosen D, Weissman IL, Longo FM, Rabinowitz JD, Andreasson KI. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature. 2021 Feb;590(7844):122-128. Epub 2021 Jan 20 PubMed.

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