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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  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 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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  1. Myeloid Metabolic Crisis May Trigger Cognitive Decline in Aging Brain