BACKGROUND: Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood. METHODS: We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. RESULTS: We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. CONCLUSION: Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.

Department of Neurology Palacky University Zdravotníků 7 Olomouc 779 00 Czech Republic

Department of Neurology University Hospital Olomouc Zdravotníků 7 Olomouc 779 00 Czech Republic

Institute of Neuroimmunology Slovak Academy of Sciences Dúbravská cesta 9 Bratislava 845 10 Slovak Republic

Laboratory for Inherited Metabolic Disorders Department of Clinical Biochemistry University Hospital Olomouc and Faculty of Medicine and Dentistry Palacký University Olomouc Zdravotníků 7 Olomouc 779 00 Czech Republic

See more in PubMed

Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers. 2015;1:15056. doi: 10.1038/nrdp.2015.56. PubMed DOI

Iqbal K, del Alonso C, Chen A, Chohan S, El-Akkad MO, Gong E. C-X, Tau pathology in Alzheimer disease and other tauopathies. Biochimica et Biophysica Acta (BBA) - molecular basis of Disease. 2005;1739:198–210. PubMed

Avila J. Tau aggregation into fibrillar polymers: taupathies. FEBS Lett. 2000;476:89–92. doi: 10.1016/S0014-5793(00)01676-8. PubMed DOI

Cantrelle F-X, Loyens A, Trivelli X, Reimann O, Despres C, Gandhi NS et al. Phosphorylation and O-GlcNAcylation of the PHF-1 epitope of tau protein induce local conformational changes of the C-Terminus and modulate tau self-assembly into Fibrillar aggregates. Front Mol Neurosci. 2021;14. PubMed PMC

Kawarabayashi T. Dimeric amyloid protein rapidly accumulates in lipid rafts followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 mouse model of Alzheimer’s Disease. J Neurosci. 2004;24:3801–9. doi: 10.1523/JNEUROSCI.5543-03.2004. PubMed DOI PMC

Gellermann GP, Appel TR, Davies P, Diekmann S. Paired helical filaments contain small amounts of cholesterol, phosphatidylcholine and sphingolipids. Biol Chem. 2006;387. PubMed

Lee JH, Han J, Woo JH, Jou I. 25-Hydroxycholesterol suppress IFN-γ-induced inflammation in microglia by disrupting lipid raft formation and caveolin-mediated signaling endosomes. Free Radic Biol Med. 2022;179:252–65. doi: 10.1016/j.freeradbiomed.2021.11.017. PubMed DOI

Song C, Manku MS, Horrobin DF. Long-chain polyunsaturated fatty acids modulate Interleukin-1β–Induced Changes in Behavior, Monoaminergic Neurotransmitters, and brain inflammation in rats. J Nutr. 2008;138:954–63. doi: 10.1093/jn/138.5.954. PubMed DOI

Don AS, Hsiao J-HT, Bleasel JM, Couttas TA, Halliday GM, Kim WS. Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun. 2014;2:150. doi: 10.1186/s40478-014-0150-6. PubMed DOI PMC

Bohdanowicz M, Grinstein S. Role of phospholipids in Endocytosis, phagocytosis, and Macropinocytosis. Physiol Rev. 2013;93:69–106. doi: 10.1152/physrev.00002.2012. PubMed DOI

Fanni AM, Vander Zanden CM, Majewska PV, Majewski J, Chi EY. Membrane-mediated fibrillation and toxicity of the tau hexapeptide PHF6. J Biol Chem. 2019;294:15304–17. doi: 10.1074/jbc.RA119.010003. PubMed DOI PMC

Kolczynska K, Loza-Valdes A, Hawro I, Sumara G. Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review. Lipids Health Dis. 2020;19:113. doi: 10.1186/s12944-020-01286-8. PubMed DOI PMC

Newton AC. Lipid activation of protein kinases. J Lipid Res. 2009;50:S266–71. doi: 10.1194/jlr.R800064-JLR200. PubMed DOI PMC

Karunakaran I, Alam S, Jayagopi S, Frohberger SJ, Hansen JN, Kuehlwein J, et al. Neural sphingosine 1-phosphate accumulation activates microglia and links impaired autophagy and inflammation. Glia. 2019;67:1859–72. doi: 10.1002/glia.23663. PubMed DOI

Filipcik P, Zilka N, Bugos O, Kucerak J, Koson P, Novak P et al. First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol Aging [Internet]. 2012;33:1448–56. 10.1016/j.neurobiolaging.2010.10.015. PubMed

Majerova P, Olesova D, Golisova G, Buralova M, Michalicova A, Vegh J et al. Analog of kynurenic acid decreases tau pathology by modulating astrogliosis in rat model for tauopathy. Biomedicine & Pharmacotherapy [Internet]. 2022;152:113257. Available from: http://biorxiv.org/content/early/2022/04/19/2022.04.19.488739.abstract. PubMed

Xuan Q, Hu C, Yu D, Wang L, Zhou Y, Zhao X, et al. Development of a high Coverage Pseudotargeted Lipidomics Method based on Ultra-high Performance Liquid Chromatography–Mass Spectrometry. Anal Chem. 2018;90:7608–16. doi: 10.1021/acs.analchem.8b01331. PubMed DOI PMC

Drotleff B, Roth SR, Henkel K, Calderón C, Schlotterbeck J, Neukamm MA, et al. Lipidomic profiling of non-mineralized dental plaque and biofilm by untargeted UHPLC-QTOF-MS/MS and SWATH acquisition. Anal Bioanal Chem. 2020;412:2303–14. doi: 10.1007/s00216-019-02364-2. PubMed DOI PMC

Yuan M, Breitkopf SB, Yang X, Asara JM. A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat Protoc. 2012;7:872–81. doi: 10.1038/nprot.2012.024. PubMed DOI PMC

Puris E, Kouřil Š, Najdekr L, Auriola S, Loppi S, Korhonen P, et al. Metabolomic, Lipidomic and Proteomic Characterisation of Lipopolysaccharide-induced inflammation mouse model. Neuroscience. 2022;496:165–78. doi: 10.1016/j.neuroscience.2022.05.030. PubMed DOI

Zilkova M, Zilka N, Kovac A, Kovacech B, Skrabana R, Skrabanova M, et al. Hyperphosphorylated Truncated protein tau induces Caspase-3 independent apoptosis-like Pathway in the Alzheimer’s Disease Cellular Model. J Alzheimer’s Disease. 2011;23:161–9. doi: 10.3233/JAD-2010-101434. PubMed DOI

Lee VM-Y, Wang J, Trojanowski JQ. [6] purification of paired helical filament tau and normal tau from human brain tissue. Methods in Enyzmologzy. Academic; 1999. pp. 81–9. PubMed

Gardlo A, Friedecký D, Najdekr L, Karlíková R, Adam T. Metabol: The statistical analysis of metabolomic data. 2019.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Res. 2003;13:2498–504. doi: 10.1101/gr.1239303. PubMed DOI PMC

Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res. 2018;46:W486–94. doi: 10.1093/nar/gky310. PubMed DOI PMC

Molenaar MR, Jeucken A, van de Wassenaar TA, Brouwers JF, Helms JB. LION/web: a web-based ontology enrichment tool for lipidomic data analysis. Gigascience. 2019;8. PubMed PMC

Barthélemy NR, Bateman RJ, Hirtz C, Marin P, Becher F, Sato C, et al. Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer’s disease and PET amyloid-positive patient identification. Alzheimers Res Ther. 2020;12:26. doi: 10.1186/s13195-020-00596-4. PubMed DOI PMC

Tumati S, Opmeer EM, Marsman J-BC, Martens S, Reesink FE, De Deyn PP, et al. Lower Choline and Myo-Inositol in Temporo-Parietal cortex is Associated with apathy in Amnestic MCI. Front Aging Neurosci. 2018;10:1–9. doi: 10.3389/fnagi.2018.00106. PubMed DOI PMC

Huang W, Ph D, Alexander GE, Daly EM, Shetty HU, Krasuski JS, et al. High brain myo-inositol levels in the Predementia phase of Alzheimer ’ s disease in adults with down ’ s syndrome. Am J Psychiatry. 1999;156:1879–86. doi: 10.1176/ajp.156.12.1879. PubMed DOI

Sajja VSSS, Perrine SA, Ghoddoussi F, Hall CS, Galloway MP, VandeVord PJ. Blast neurotrauma impairs working memory and disrupts prefrontal myo-inositol levels in rats. Molecular and Cellular Neuroscience [Internet]. 2014 [cited 2018 May 13];59:119–26. Available from: https://www.sciencedirect.com/science/article/pii/S1044743114000232?via%3Dihub. PubMed

Aksenov M, Aksenova M, Butterfield DA, Markesbery WR. Oxidative Modification of Creatine Kinase BB in Alzheimer’s Disease Brain. J Neurochem. 2002;74:2520–7. doi: 10.1046/j.1471-4159.2000.0742520.x. PubMed DOI

Barnes VM, Teles R, Trivedi HM, Devizio W, Xu T, Mitchell MW, et al. Acceleration of Purine Degradation by Periodontal diseases. J Dent Res. 2009;88:851–5. doi: 10.1177/0022034509341967. PubMed DOI

Yan X, Hu Y, Wang B, Wang S, Zhang X. Metabolic dysregulation contributes to the progression of Alzheimer’s Disease. Front Neurosci. 2020;14. PubMed PMC

Westergaard N, Sonnewald U, Unsgård G, Peng L, Hertz L, Schousboe A. Uptake, Release, and Metabolism of Citrate in Neurons and Astrocytes in Primary Cultures. J Neurochem [Internet]. 1994;62:1727–33. 10.1046/j.1471-4159.1994.62051727.x. PubMed

Pascente R, Frigerio F, Rizzi M, Porcu L, Boido M, Davids J, et al. Cognitive deficits and brain myo-inositol are early biomarkers of epileptogenesis in a rat model of epilepsy. Neurobiol Dis. 2016;93:146–55. doi: 10.1016/j.nbd.2016.05.001. PubMed DOI

Sweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–50. doi: 10.1038/nrneurol.2017.188. PubMed DOI PMC

Clarke JR, Ribeiro FC, Frozza RL, De Felice FG, Lourenco MV. Metabolic Dysfunction in Alzheimer’s Disease: From Basic Neurobiology to Clinical Approaches. Perry G, Avila J, Moreira PI, Sorensen AA, Tabaton M, editors. Journal of Alzheimer’s Disease. 2018;64:S405–26. PubMed

Villamil-Ortiz JG, Barrera-Ocampo A, Arias-Londoño JD, Villegas A, Lopera F, Cardona-Gómez GP. Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A-Familiar and Sporadic Alzheimer’s Disease Brains. Journal of Alzheimer’s Disease [Internet]. 2017;61:209–19. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JAD-170554 PubMed

Whiley L, Sen A, Heaton J, Proitsi P, García-Gómez D, Leung R et al. Evidence of altered phosphatidylcholine metabolism in Alzheimer’s disease. Neurobiol Aging [Internet]. 2014 [cited 2020 Feb 7];35:271–8. Available from: https://www.sciencedirect.com/science/article/pii/S0197458013003357?via%3Dihub. PubMed PMC

Huynh K, Lim WLF, Giles C, Jayawardana KS, Salim A, Mellett NA, et al. Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease. Nat Commun. 2020;11:5698. doi: 10.1038/s41467-020-19473-7. PubMed DOI PMC

Liu Q, Zhang J. Lipid metabolism in Alzheimer’s disease. Neurosci Bull [Internet]. 2014;30:331–45. Available from: http://link.springer.com/10.1007/s12264-013-1410-3. PubMed PMC

Tan ST, Ramesh T, Toh XR, Nguyen LN. Emerging roles of lysophospholipids in health and disease. Prog Lipid Res. 2020;80:101068. doi: 10.1016/j.plipres.2020.101068. PubMed DOI

Sagy-Bross C, Hadad N, Levy R. Cytosolic phospholipase A2α upregulation mediates apoptotic neuronal death induced by aggregated amyloid-β peptide 1–42. Neurochem Int. 2013;63:541–50. doi: 10.1016/j.neuint.2013.09.007. PubMed DOI

Sabogal-Guáqueta AM, Villamil-Ortiz JG, Arias-Londoño JD, Cardona-Gómez GP. Inverse Phosphatidylcholine/Phosphatidylinositol Levels as Peripheral Biomarkers and Phosphatidylcholine/Lysophosphatidylethanolamine-Phosphatidylserine as hippocampal Indicator of Postischemic Cognitive impairment in rats. Front Neurosci. 2018;12. PubMed PMC

Tzekov R, Dawson C, Orlando M, Mouzon B, Reed J, Evans J et al. Sub-Chronic Neuropathological and Biochemical Changes in Mouse Visual System after Repetitive Mild Traumatic Brain Injury. Chidlow G, editor. PLoS One. 2016;11:e0153608. PubMed PMC

Palavicini JP, Wang C, Chen L, Hosang K, Wang J, Tomiyama T, et al. Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A2 in a spatial-specific manner. Acta Neuropathol Commun. 2017;5:56. doi: 10.1186/s40478-017-0460-6. PubMed DOI PMC

Sheikh AM, Nagai A. Lysophosphatidylcholine modulates fibril formation of amyloid beta peptide. FEBS J. 2011;278:634–42. doi: 10.1111/j.1742-4658.2010.07984.x. PubMed DOI

Pedersen JN, Jiang Z, Christiansen G, Lee JC, Pedersen JS, Otzen DE. Lysophospholipids induce fibrillation of the repeat domain of Pmel17 through intermediate core-shell structures. Biochim et Biophys Acta (BBA) - Proteins Proteom. 2019;1867:519–28. doi: 10.1016/j.bbapap.2018.11.007. PubMed DOI PMC

Liu G-Y, Moon SH, Jenkins CM, Sims HF, Guan S, Gross RW. A functional role for eicosanoid-lysophospholipids in activating monocyte signaling. J Biol Chem. 2020;295:12167–80. doi: 10.1074/jbc.RA120.013619. PubMed DOI PMC

Xu J, Wang T, Wu Y, Jin W, Wen Z. Microglia colonization of developing zebrafish midbrain is promoted by Apoptotic Neuron and Lysophosphatidylcholine. Dev Cell. 2016;38:214–22. doi: 10.1016/j.devcel.2016.06.018. PubMed DOI

Greiner AJ, Richardson RJ, Worden RM, Ofoli RY. Influence of lysophospholipid hydrolysis by the catalytic domain of neuropathy target esterase on the fluidity of bilayer lipid membranes. Biochimica et Biophysica Acta (BBA) Biomembranes. 2010;1798:1533–9. doi: 10.1016/j.bbamem.2010.03.015. PubMed DOI

Zilka N, Stozicka Z, Kovac A, Pilipcinec E, Bugos O, Novak M. Human misfolded truncated tau protein promotes activation of microglia and leukocyte infiltration in the transgenic rat model of tauopathy. J Neuroimmunol. 2009;209:16–25. doi: 10.1016/j.jneuroim.2009.01.013. PubMed DOI

Heneka MT, Carson MJ, Khoury J, El, Landreth GE, Brosseron F, Feinstein DL et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol [Internet]. 2015;14:388–405. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1474442215700165. PubMed PMC

Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol. 2019;20:137–55. doi: 10.1038/s41580-018-0085-z. PubMed DOI PMC

Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci [Internet]. 2020;23:194–208. 10.1038/s41593-019-0566-1. PubMed PMC

den Brok MH, Raaijmakers TK, Collado-Camps E, Adema GJ. Lipid Droplets as Immune Modulators in Myeloid Cells. Trends Immunol [Internet]. 2018;39:380–92. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1471490618300231. PubMed

Nguyen TB, Louie SM, Daniele JR, Tran Q, Dillin A, Zoncu R et al. DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced Autophagy. Dev Cell [Internet]. 2017;42:9–21.e5. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1534580717304598. PubMed PMC

Asai H, Ikezu S, Woodbury ME, Yonemoto GMS, Cui L, Ikezu T. Accelerated neurodegeneration and Neuroinflammation in transgenic mice expressing P301L tau mutant and Tau-Tubulin Kinase 1. Am J Pathol. 2014;184:808–18. doi: 10.1016/j.ajpath.2013.11.026. PubMed DOI PMC

Kovac A, Zilka N, Kazmerova Z, Cente M, Zilkova M, Novak M. Misfolded truncated protein τ induces Innate Immune Response via MAPK Pathway. J Immunol. 2011;187:2732–9. doi: 10.4049/jimmunol.1100216. PubMed DOI

Tu R, Yang W, Hu Z. Inhibition of sphingomyelin synthase 1 affects ceramide accumulation and hydrogen peroxide-induced apoptosis in Neuro-2a cells. NeuroReport. 2016;27:967–73. doi: 10.1097/WNR.0000000000000639. PubMed DOI

Malaplate-Armand C, Florent-Béchard S, Youssef I, Koziel V, Sponne I, Kriem B, et al. Soluble oligomers of amyloid-β peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis. 2006;23:178–89. doi: 10.1016/j.nbd.2006.02.010. PubMed DOI

Mielke MMMM, Haughey NJNJ, Bandaru VVR, Zetterberg H, Blennow K, Andreasson U, et al. Cerebrospinal fluid sphingolipids, β-amyloid, and tau in adults at risk for Alzheimer’s disease. Neurobiol Aging. 2014;35:2486–94. doi: 10.1016/j.neurobiolaging.2014.05.019. PubMed DOI PMC

Murray NR, Fields AP. Phosphatidylglycerol is a physiologic activator of nuclear protein kinase C. J Biol Chem. 1998;273:11514–20. doi: 10.1074/jbc.273.19.11514. PubMed DOI

Muraleedharan A, Rotem-Dai N, Strominger I, Anto NP, Isakov N, Monsonego A, et al. Protein kinase C eta is activated in reactive astrocytes of an Alzheimer’s disease mouse model: evidence for its immunoregulatory function in primary astrocytes. Glia. 2021;69:697–714. doi: 10.1002/glia.23921. PubMed DOI

Kim H-Y, Huang BX, Spector AA. Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res. 2014;56:1–18. doi: 10.1016/j.plipres.2014.06.002. PubMed DOI PMC

Correas I, Díaz-Nido J, Avila J. Microtubule-associated protein tau is phosphorylated by protein kinase C on its tubulin binding domain. J Biol Chem. 1992;267:15721–8. doi: 10.1016/S0021-9258(19)49595-1. PubMed DOI

Zhang X, Liu W, Cao Y, Tan W. Hippocampus Proteomics and Brain Lipidomics Reveal Network Dysfunction and Lipid Molecular Abnormalities in APP/PS1 mouse model of Alzheimer’s Disease. J Proteome Res. 2020;19:3427–37. doi: 10.1021/acs.jproteome.0c00255. PubMed DOI

Chan RB, Oliveira TG, Cortes EP, Honig LS, Duff KE, Small SA, et al. Comparative lipidomic analysis of mouse and human brain with Alzheimer Disease. J Biol Chem. 2012;287:2678–88. doi: 10.1074/jbc.M111.274142. PubMed DOI PMC

Nitsch RM, Blusztajn JK, Pittas AG, Slack BE, Growdon JH, Wurtman RJ. Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci U S A. 1992;89:1671–5. doi: 10.1073/pnas.89.5.1671. PubMed DOI PMC

Kopeikina KJ, Carlson GA, Pitstick R, Ludvigson AE, Peters A, Luebke JI, et al. Tau Accumulation causes mitochondrial distribution deficits in neurons in a mouse model of Tauopathy and in human Alzheimer’s Disease Brain. Am J Pathol. 2011;179:2071–82. doi: 10.1016/j.ajpath.2011.07.004. PubMed DOI PMC

Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hinerfeld D, et al. Mitochondrial oxidative stress causes hyperphosphorylation of tau. Khoury J El Editor PLoS One. 2007;2:e536. doi: 10.1371/journal.pone.0000536. PubMed DOI PMC

Ramírez Ríos S, Lamarche F, Cottet-Rousselle C, Klaus A, Tuerk R, Thali R et al. Regulation of brain-type creatine kinase by AMP-activated protein kinase: Interaction, phosphorylation and ER localization. Biochimica et Biophysica Acta (BBA) - Bioenergetics [Internet]. 2014;1837:1271–83. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0005272814001091. PubMed

Fecher C, Trovò L, Müller SA, Snaidero N, Wettmarshausen J, Heink S, et al. Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity. Nat Neurosci. 2019;22:1731–42. doi: 10.1038/s41593-019-0479-z. PubMed DOI

Eraso-Pichot A, Brasó-Vives M, Golbano A, Menacho C, Claro E, Galea E, et al. GSEA of mouse and human mitochondriomes reveals fatty acid oxidation in astrocytes. Glia. 2018;66:1724–35. doi: 10.1002/glia.23330. PubMed DOI

Ioannou MS, Jackson J, Sheu S-H, Chang C-L, Weigel Av, Liu H et al. Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity. Cell [Internet]. 2019;177:1522–1535.e14. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0092867419303873. PubMed

Schönfeld P, Reiser G. Brain energy metabolism spurns fatty acids as fuel due to their inherent mitotoxicity and potential capacity to unleash neurodegeneration. Neurochem Int [Internet]. 2017;109:68–77. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0197018617301092. PubMed

Pan X, Nasaruddin M, Bin, Elliott CT, McGuinness B, Passmore AP, Kehoe PG, et al. Alzheimer’s disease–like pathology has transient effects on the brain and blood metabolome. Neurobiol Aging. 2016;38:151–63. doi: 10.1016/j.neurobiolaging.2015.11.014. PubMed DOI

Longo N, Frigeni M, Pasquali M. Carnitine transport and fatty acid oxidation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research [Internet]. 2016;1863:2422–35. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0167488916300131. PubMed PMC

Abdul HM, Calabrese V, Calvani M, Butterfield DA. Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1–42-mediated oxidative stress and neurotoxicity: Implications for Alzheimer’s disease. J Neurosci Res [Internet]. 2006;84:398–408. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jnr.20877. PubMed

Manzo E, O’Conner AG, Barrows JM, Shreiner DD, Birchak GJ, Zarnescu DC. Medium-chain fatty acids, Beta-hydroxybutyric acid and genetic modulation of the Carnitine Shuttle are Protective in a Drosophila model of ALS based on TDP-43. Front Mol Neurosci. 2018;11. PubMed PMC