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01-12-2020 | Alzheimer's Disease | Short report

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology

Authors: Daniel C. Shippy, Connor Wilhelm, Patel A. Viharkumar, Thomas J. Raife, Tyler K. Ulland

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

Alzheimer’s disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

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Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119–28.PubMedPubMedCentralCrossRef

de la Monte SM, Tong M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol. 2014;88:548–59.PubMedCrossRef

Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, et al. TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell. 2017;170:649–63 e613.PubMedPubMedCentralCrossRef

Gotzl JK, Brendel M, Werner G, Parhizkar S, Sebastian Monasor L, Kleinberger G, et al. Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism. EMBO Mol Med. 2019;11.

Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017;36:1837–53.PubMedPubMedCentralCrossRef

Holtzman DM, Morris JC, Goate AM. Alzheimer's disease: the challenge of the second century. Sci Transl Med. 2011;3:77sr71.

Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213:667–75.PubMedPubMedCentralCrossRef

Sarlus H, Heneka MT. Microglia in Alzheimer's disease. J Clin Invest. 2017;127:3240–9.PubMedPubMedCentralCrossRef

Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer's disease. Nature. 2017;552:355–61.PubMedCrossRef

10.

Ulrich JD, Ulland TK, Mahan TE, Nystrom S, Nilsson KP, Song WM, et al. ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med. 2018;215:1047–58.PubMedPubMedCentralCrossRef

11.

Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 2016;90:724–39.PubMedPubMedCentralCrossRef

12.

Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015;14:388–405.PubMedPubMedCentralCrossRef

13.

Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8.PubMedCrossRef

14.

Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 2004;25:311–4.PubMedCrossRef

15.

Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond). 2009;6:31.CrossRef

16.

Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging. 2012;33:425 e419–27.CrossRef

17.

Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease. Alzheimers Dement (N Y). 2018;4:28–36.CrossRef

18.

Ota M, Matsuo J, Ishida I, Takano H, Yokoi Y, Hori H, et al. Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function in patients with mild-to-moderate Alzheimer's disease. Neurosci Lett. 2019;690:232–6.PubMedCrossRef

19.

Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, et al. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Neurobiol Aging. 2013;34:1530–9.PubMedCrossRef

20.

Klein C, Mathis C, Leva G, Patte-Mensah C, Cassel JC, Maitre M, et al. Gamma-Hydroxybutyrate (Xyrem) ameliorates clinical symptoms and neuropathology in a mouse model of Alzheimer's disease. Neurobiol Aging. 2015;36:832–44.PubMedCrossRef

21.

Pawlosky RJ, Kemper MF, Kashiwaya Y, King MT, Mattson MP, Veech RL. Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer's disease. J Neurochem. 2017;141:195–207.PubMedPubMedCentralCrossRef

22.

Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–9.PubMedPubMedCentralCrossRef

23.

Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–40.PubMedPubMedCentralCrossRef

24.

Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement. 2015;11:718–26.PubMedCrossRef

25.

Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. J Clin Invest. 2012;122:1339–53.PubMedPubMedCentralCrossRef

26.

Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38.PubMedPubMedCentralCrossRef

27.

Zhao N, Liu CC, Van Ingelgom AJ, Martens YA, Linares C, Knight JA, et al. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron. 2017;96:115–29 e115.PubMedPubMedCentralCrossRef

28.

Kim B, Elzinga SE, Henn RE, McGinley LM, Feldman EL. The effects of insulin and insulin-like growth factor I on amyloid precursor protein phosphorylation in in vitro and in vivo models of Alzheimer's disease. Neurobiol Dis. 2019;132:104541.PubMedCrossRefPubMedCentral

29.

Dashti HM, Mathew TC, Khadada M, Al-Mousawi M, Talib H, Asfar SK, et al. Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem. 2007;302:249–56.PubMedCrossRef

30.

Westman EC, Yancy WS Jr, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008;5:36.CrossRef

31.

Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A. 2000;97:5440–4.PubMedPubMedCentralCrossRef

32.

Kashiwaya Y, King MT, Veech RL. Substrate signaling by insulin: a ketone bodies ratio mimics insulin action in heart. Am J Cardiol. 1997;80:50A–64A.PubMedCrossRef

33.

Pierre K, Pellerin L, Debernardi R, Riederer BM, Magistretti PJ. Cell-specific localization of monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain revealed by double immunohistochemical labeling and confocal microscopy. Neuroscience. 2000;100:617–27.PubMedCrossRef

34.

Bergersen L, Rafiki A, Ottersen OP. Immunogold cytochemistry identifies specialized membrane domains for monocarboxylate transport in the central nervous system. Neurochem Res. 2002;27:89–96.PubMedCrossRef

35.

Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease. Nutr Metab (Lond). 2005;2:28.CrossRef

36.

Hoshi M, Takashima A, Noguchi K, Murayama M, Sato M, Kondo S, et al. Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci U S A. 1996;93:2719–23.PubMedPubMedCentralCrossRef

37.

Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651–8.PubMedCrossRef

38.

Yao J, Chen S, Mao Z, Cadenas E, Brinton RD. 2-deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease. PLoS One. 2011;6:e21788.PubMedPubMedCentralCrossRef

39.

Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2009;106:14670–5.PubMedPubMedCentralCrossRef

40.

Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ 42 hotspots around plaques. Nat Commun. 2015;6:6176.PubMedCrossRef

41.

Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 2015;3:136.PubMedPubMedCentral

42.

Sosna J, Philipp S, Albay R 3rd, Reyes-Ruiz JM, Baglietto-Vargas D, LaFerla FM, et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener. 2018;13:11.PubMedPubMedCentralCrossRef

43.

Sierra A, de Castro F, Del Rio-Hortega J, Rafael Iglesias-Rozas J, Garrosa M, Kettenmann H. The "big-bang" for modern glial biology: translation and comments on Pio del Rio-Hortega 1919 series of papers on microglia. Glia. 2016;64:1801–40.PubMedCrossRef

44.

Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014;10:217–24.PubMedCrossRef

45.

Davies DS, Ma J, Jegathees T, Goldsbury C. Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease. Brain Pathol. 2017;27:795–808.PubMedCrossRef

46.

Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A. Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer's disease. Aging Cell. 2014;13:584–95.PubMedPubMedCentralCrossRef

47.

Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et al. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci. 2008;28:4283–92.PubMedPubMedCentralCrossRef

48.

Koenigsknecht-Talboo J, Meyer-Luehmann M, Parsadanian M, Garcia-Alloza M, Finn MB, Hyman BT, et al. Rapid microglial response around amyloid pathology after systemic anti- Aβ antibody administration in PDAPP mice. J Neurosci. 2008;28:14156–64.PubMedPubMedCentralCrossRef

49.

Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–94.PubMedCrossRef

50.

Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009;10:241–7.PubMedPubMedCentralCrossRef

51.

Deora V, Albornoz EA, Zhu K, Woodruff TM, Gordon R. The ketone body beta-hydroxybutyrate does not inhibit synuclein mediated inflammasome activation in microglia. J NeuroImmune Pharmacol. 2017;12:568–74.PubMedCrossRef

52.

Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:535–62.PubMedPubMedCentralCrossRef

53.

Kovacs Z, Brunner B, D'Agostino DP, Ari C. Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar albino Glaxo Rijswijk rats. BMC Anesthesiol. 2020;20:30.PubMedPubMedCentralCrossRef

54.

Kovacs Z, D'Agostino DP, Dobolyi A, Ari C. Adenosine A1 receptor antagonism abolished the anti-seizure effects of exogenous ketone supplementation in Wistar albino Glaxo Rijswijk rats. Front Mol Neurosci. 2017;10:235.PubMedPubMedCentralCrossRef

55.

Caminhotto RO, Komino ACM, de Fatima SF, Andreotti S, Sertie RAL, Boltes Reis G, et al. Oral beta-hydroxybutyrate increases ketonemia, decreases visceral adipocyte volume and improves serum lipid profile in Wistar rats. Nutr Metab (Lond). 2017;14:31.CrossRef

56.

Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015;160:1061–71.PubMedPubMedCentralCrossRef

57.

Schneider CA, Rasband WS, Eliceiri KW. NIH image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.PubMedPubMedCentralCrossRef

58.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.PubMedCrossRef

Title: β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology
Authors: Daniel C. Shippy
Connor Wilhelm
Patel A. Viharkumar
Thomas J. Raife
Tyler K. Ulland
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Alzheimer's Disease
Alzheimer's Disease
Pathology
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-01948-5

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β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology

Abstract

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Abstract

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