Ischemic stroke remains a major contributor to neurological disability worldwide, with limited options for promoting brain recovery. While acetate is known to exert various pathophysiological effects on the brain, its potential to mitigate brain injury following ischemic stroke and the underlying mechanisms remain poorly understood. In particular, how acetate engage astrocyte–neuron metabolic coupling and influence tau protein modifications remains to be clarified. Here, we found that brain acetate levels were elevated by 1.51-fold after ischemia and reperfusion for 24 h. The accumulated acetate in the brain improved survival with a 7-day survival rate of 61% in the acetate group versus 47% in the control group and attenuated brain injury. Mechanistically, acetate stimulated the astrocyte-neuron lactate shuttle (ANLS), leading to increased tau protein lactylation in neurons. This process was blocked by Su3118, a pharmacological inhibitor of monocarboxylate transporter 1/4 (MCT1/4), confirming their involvement. We further revealed that site-specific tau lactylation enhanced neuronal plasticity and rendered the brain less sensitive to ischemic stroke. Taken together, our findings unveil that acetate enhances astrocytic glucose uptake and glycolysis, stimulates ANLS, and promotes tau protein lactylation in neurons, thereby contributing to its neuroprotective role, highlighting its relevance for developing acetate-based interventions in stroke recovery.
ViraniSSAlonsoABenjaminEJ, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation2020; 141: e139–e596.
2.
GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol2021; 20: 795–820.
3.
WeaverNAKuijfHJAbenHP, et al. Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts. Lancet Neurol2021; 20: 448–459.
4.
FanJLiXYuX, et al. Global burden, risk factors analysis, and prediction study of ischemic stroke, 1990–2030. Neurology2023; 101(2): e137–e150.
5.
GaoXLinSHRenF, et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun2016; 7: 11960.
6.
FlintHJDuncanSHScottKP, et al. Links between diet, gut microbiota composition and gut metabolism. Proc Nutr Soc2015; 74: 13–22.
7.
ChambersESMorrisonDJFrostG.Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms?Proc Nutr Soc2015; 74: 328–336.
8.
WyssMTMagistrettiPJBuckA, et al. Labeled acetate as a marker of astrocytic metabolism. J Cereb Blood Flow Metab2011; 31: 1668–1674.
9.
LouisPHoldGLFlintHJ.The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol2014; 12: 661–672.
10.
SmithMDBhattDPGeigerJD, et al. Acetate supplementation modulates brain adenosine metabolizing enzymes and adenosine A2A receptor levels in rats subjected to neuroinflammation. J Neuroinflammation2014; 11: 99.
11.
ZhengHXuPJiangQ, et al. Depletion of acetate-producing bacteria from the gut microbiota facilitates cognitive impairment through the gut-brain neural mechanism in diabetic mice. Microbiome2021; 9: 145.
12.
SoPWEkonomouAGalleyK, et al. Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke. Int J Nanomed2019; 14: 1979–1991.
13.
ArunPAriyannurPSMoffettJR, et al. Metabolic acetate therapy for the treatment of traumatic brain injury. J Neurotrauma2010; 27: 293–298.
14.
GeocadinRGCallawayCWFinkEL, et al. Standards for studies of neurological prognostication in comatose survivors of cardiac arrest: a scientific statement from the American Heart Association. Circulation2019; 140: e517–e542.
15.
BarrosLFBrownASwansonRA.Glia in brain energy metabolism: a perspective. Glia2018; 66: 1134–1137.
16.
JhaMKMorrisonBM.Glia-neuron energy metabolism in health and diseases: new insights into the role of nervous system metabolic transporters. Exp Neurol2018; 309: 23–31.
17.
OberheimNAWangXGoldmanS, et al. Astrocytic complexity distinguishes the human brain. Trends Neurosci2006; 29: 547–553.
18.
GordonGRChoiHBRungtaRL, et al. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature2008; 456: 745–749.
19.
PerryRJPengLBarryNA, et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature2016; 534: 213–217.
20.
ShishehborFMansooriAShiraniF.Vinegar consumption can attenuate postprandial glucose and insulin responses; a systematic review and meta-analysis of clinical trials. Diabetes Res Clin Pract2017; 127: 1–9.
21.
HallCNKlein-FlüggeMCHowarthC, et al. Oxidative phosphorylation, not glycolysis, powers presynaptic and postsynaptic mechanisms underlying brain information processing. J Neurosci2012; 32: 8940–8951.
22.
BittnerCXValdebenitoRRuminotI, et al. Fast and reversible stimulation of astrocytic glycolysis by K+ and a delayed and persistent effect of glutamate. J Neurosci2011; 31: 4709–4713.
23.
ViegasFONeuhaussSCF. A metabolic landscape for maintaining retina integrity and function. Front Mol Neurosci2021; 14: 656000.
24.
KangBSChoiBYKhoAR, et al. Effects of pyruvate kinase M2 (PKM2) gene deletion on astrocyte-specific glycolysis and global cerebral ischemia-induced neuronal death. Antioxidants2023; 12(2): 491.
25.
HaselPAisenbergWHBennettFC, et al. Molecular and metabolic heterogeneity of astrocytes and microglia. Cell Metab2023; 35: 555–570.
26.
LiFSamiANoristaniHN, et al. Glial metabolic rewiring promotes axon regeneration and functional recovery in the central nervous system. Cell Metab2020; 32: 767–785.e767.
27.
LiXYangYZhangB, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther2022; 7: 305.
28.
HagiharaHShojiHOtabiH, et al. Protein lactylation induced by neural excitation. Cell Rep2021; 37: 109820.
29.
LiuRWuJGuoH, et al. Post-translational modifications of histones: mechanisms, biological functions, and therapeutic targets. MedComm2023; 4: e292.
30.
FujiiHTakahashiTMukaiT, et al. Modifications of tau protein after cerebral ischemia and reperfusion in rats are similar to those occurring in Alzheimer’s disease—hyperphosphorylation and cleavage of 4- and 3-repeat tau. J Cereb Blood Flow Metab2017; 37: 2441–2457.
31.
LuoLAmbrozkiewiczMCBenselerF, et al. Optimizing nervous system-specific gene targeting with Cre driver lines: prevalence of germline recombination and influencing factors. Neuron2020; 106: 37–65.e35.
32.
HowardDMAdamsMJClarkeTK, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci2019; 22: 343–352.
33.
Bulik-SullivanBKLohPRFinucaneHK, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet2015; 47: 291–295.
34.
ShubitowskiTBPollBGNatarajanN, et al. Short-chain fatty acid delivery: assessing exogenous administration of the microbiome metabolite acetate in mice. Physiol Rep2019; 7: e14005.
35.
TuoQZLeiPJackmanKA, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry2017; 22: 1520–1530.
36.
ZhangBZhangHXShiST, et al. Interleukin-11 treatment protected against cerebral ischemia/reperfusion injury. Biomed Pharmacother2019; 115: 108816.
37.
FengDWangBWangL, et al. Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings. J Pineal Res2017; 62(3): e12395.
38.
WangPXuTYWeiK, et al. ARRB1/β-arrestin-1 mediates neuroprotection through coordination of BECN1-dependent autophagy in cerebral ischemia. Autophagy2014; 10: 1535–1548.
39.
ChenCLiuCNiuZ, et al. RNA-seq analysis of the key long noncoding RNAs and mRNAs related to cognitive impairment after cardiac arrest and cardiopulmonary resuscitation. Aging2020; 12: 14490–14505.
40.
LegerMQuiedevilleABouetV, et al. Object recognition test in mice. Nat Protoc2013; 8: 2531–2537.
41.
LiuXZhangYDengY, et al. Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice. J Mol Cell Cardiol2022; 165: 76–85.
42.
DienelGA.Brain glucose metabolism: integration of energetics with function. Physiol Rev2019; 99: 949–1045.
43.
MagistrettiPJAllamanI.Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci2018; 19: 235–249.
44.
AllamanIBélangerMMagistrettiPJ.Astrocyte–neuron metabolic relationships: for better and for worse. Trends Neurosci2011; 34: 76–87.
45.
MagistrettiPJAllamanI.A cellular perspective on brain energy metabolism and functional imaging. Neuron2015; 86: 883–901.
46.
ZhangDTangZHuangH, et al. Metabolic regulation of gene expression by histone lactylation. Nature2019; 574: 575–580.
47.
PanRYHeLZhangJ, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab2022; 34: 634–648.e636.
48.
LinQHaiJYaoLY, et al. Neuroprotective effects of NSTyr on cognitive function and neuronal plasticity in rats of chronic cerebral hypoperfusion. Brain Res2010; 1325: 183–190.
49.
YangXYGengLLiR, et al. Huperzine A-liposomes efficiently improve neural injury in the hippocampus of mice with chronic intermittent hypoxia. Int J Nanomedicine2023; 18: 843–859.
50.
SonnewaldUSchousboeAQuH, et al. Intracellular metabolic compartmentation assessed by 13C magnetic resonance spectroscopy. Neurochem Int2004; 45: 305–310.
51.
PellerinLBouzier-SoreAKAubertA, et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia2007; 55: 1251–1262.
MoelleringRECravattBF.Functional lysine modification by an intrinsically reactive primary glycolytic metabolite. Science2013; 341: 549–553.
54.
TauffenbergerAFiumelliHAlmustafaS, et al. Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling. Cell Death Dis2019; 10: 653.
55.
BerthetCLeiHThevenetJ, et al. Neuroprotective role of lactate after cerebral ischemia. J Cereb Blood Flow Metab2009; 29: 1780–1789.
56.
BerthetCCastilloXMagistrettiPJ, et al. New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration. Cerebrovasc Dis2012; 34: 329–335.
57.
SchurrAPayneRSMillerJJ, et al. Brain lactate is an obligatory aerobic energy substrate for functional recovery after hypoxia: further in vitro validation. J Neurochem1997; 69: 423–426.
58.
ChenXJiangH.Tau as a potential therapeutic target for ischemic stroke. Aging2019; 11: 12827–12843.
59.
ReganPWhitcombDJChoK.Physiological and pathophysiological implications of synaptic tau. Neuroscientist2017; 23: 137–151.
60.
YiSLiuQWangX, et al. Tau modulates Schwann cell proliferation, migration and differentiation following peripheral nerve injury. J Cell Sci2019; 132(6): jcs222059.
61.
KollerEJChakrabartyP.Tau-mediated dysregulation of neuroplasticity and glial plasticity. Front Mol Neurosci2020; 13: 151.
62.
WeingartenMDLockwoodAHHwoSY, et al. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A1975; 72: 1858–1862.
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