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BACE1 influences clinical manifestations and central inflammation in relapsing remitting multiple sclerosis

Published:January 23, 2023DOI:https://doi.org/10.1016/j.msard.2023.104528

      Highlights

      • CSF BACE1 levels are associated with depression and worse visual-spatial memory performance in RR-MS patients.
      • Higher levels of BACE1 correlate with worse prognosis and disease course of RR-MS patients.
      • BACE1 influences a group of neuroinflammatory mediators in RR-MS.
      • BACE1 is involved in mitochondrial dysfunction and oxidative stress mechanisms at the basis of MS pathophysiology.
      • BACE1 CSF levels correlate with neurodegenerative biomarkers including p-Tau and Aβ 1-42/1-40 ratio, a biomarker of Aβ pathology burden.

      Abstract

      Neurodegenerative and inflammatory processes influence the clinical course of multiple sclerosis (MS). The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been associated with cognitive dysfunction, amyloid deposition and neuroinflammation in Alzheimer's disease.
      We explored in a group of 50 patients with relapsing-remitting MS the association between the cerebrospinal fluid (CSF) levels of BACE1, clinical characteristics at the time of diagnosis and prospective disability after three-years follow-up. In addition, we assessed the correlations between the CSF levels of BACE 1, amyloid β (Aβ) 1-40 and 1-42, phosphorylated tau (pTau), lactate, and a set of inflammatory and anti-inflammatory molecules.
      BACE1 CSF levels were correlated positively with depression as measured with Beck Depression Inventory–Second Edition scale, and negatively with visuospatial memory performance evaluated by the Brief Visuospatial Memory Test-Revised. In addition, BACE CSF levels were positively correlated with Bayesian Risk Estimate for MS at onset, and with Expanded Disability Status Scale score assessed three years after diagnosis. Furthermore, a positive correlation was found between BACE1, amyloid β 42/40 ratio (Spearman's r = 0.334, p = 0.018, n = 50), pTau (Spearman's r = 0.304, p = 0.032, n = 50) and lactate concentrations (Spearman's r = 0.361, p = 0.01, n = 50). Finally, an association emerged between BACE1 CSF levels and a group of pro and anti-inflammatory molecules, including interleukin (IL)-4, IL-17, IL-13, IL-9 and interferon-γ.
      BACE1 may have a role in different key mechanisms such as neurodegeneration, oxidative stress and inflammation, influencing mood, cognitive disorders and disability progression in MS.

      Keywords

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      References

        • Albanese M.
        • Zagaglia S.
        • Landi D.
        • Boffa L.
        • Nicoletti C.G.
        • Marciani M.G.
        • Mandolesi G.
        • Marfia G.A.
        • Buttari F.
        • Mori F.
        • Centonze D.
        Cerebrospinal fluid lactate is associated with multiple sclerosis disease progression.
        J. Neuroinflammation. 2016; 13: 36https://doi.org/10.1186/s12974-016-0502-1
        • Baiardi S.
        • Abu-Rumeileh S.
        • Rossi M.
        • Zenesini C.
        • Bartoletti-Stella A.
        • Polischi B.
        • Capellari S.
        • Parchi P.
        Antemortem CSF A β 42/A β 40 ratio predicts Alzheimer's disease pathology better than A β 42 in rapidly progressive dementias.
        Ann. Clin. Transl. Neurol. acn3. 2018; 697https://doi.org/10.1002/acn3.697
        • Barcelos I.P.de
        • Troxell R.M.
        • Graves J.S.
        Mitochondrial Dysfunction and Multiple Sclerosis.
        Biology (Basel). 2019; 8: 37https://doi.org/10.3390/biology8020037
        • Bergamaschi R.
        • Montomoli C.
        • Mallucci G.
        • Lugaresi A.
        • Izquierdo G.
        • Grand'Maison F.
        • Duquette P.
        • Shaygannejad V.
        • Alroughani R.
        • Grammond P.
        • Boz C.
        • Iuliano G.
        • Zwanikken C.
        • Petersen T.
        • Lechner-Scott J.
        • Hupperts R.
        • Butzkueven H.
        • Pucci E.
        • Oreja-Guevara C.
        • Cristiano E.
        • Pia Amato M.P.
        • Havrdova E.
        • Fernandez-Bolanos R.
        • Spelman T.
        • Trojano M.
        BREMSO: a simple score to predict early the natural course of multiple sclerosis.
        Eur. J. Neurol. 2015; 22: 981-989https://doi.org/10.1111/ene.12696
        • Binzer S.
        • McKay K.A.
        • Brenner P.
        • Hillert J.
        • Manouchehrinia A.
        Disability worsening among persons with multiple sclerosis and depression.
        Neurology. 2019; 93: e2216-e2223https://doi.org/10.1212/WNL.0000000000008617
        • Cole S.L.
        • Vassar R.
        The Alzheimer's disease Beta-secretase enzyme, BACE1.
        Mol. Neurodegener. 2007; 2: 22https://doi.org/10.1186/1750-1326-2-22
        • Diker S.
        • Has A.C.
        • Kurne A.
        • Göçmen R.
        • Oğuz K.K.
        • Karabudak R.
        The association of cognitive impairment with gray matter atrophy and cortical lesion load in clinically isolated syndrome.
        Mult. Scler. Relat. Disord. 2016; 10: 14-21https://doi.org/10.1016/j.msard.2016.08.008
        • Eshaghi A.
        • Marinescu R.V
        • Young A.L.
        • Firth N.C.
        • Prados F.
        • Jorge Cardoso M.
        • Tur C.
        • De Angelis F.
        • Cawley N.
        • Brownlee W.J.
        • De Stefano N.
        • Laura Stromillo M.
        • Battaglini M.
        • Ruggieri S.
        • Gasperini C.
        • Filippi M.
        • Rocca M.A.
        • Rovira A.
        • Sastre-Garriga J.
        • Geurts J.J.G.
        • Vrenken H.
        • Wottschel V.
        • Leurs C.E.
        • Uitdehaag B.
        • Pirpamer L.
        • Enzinger C.
        • Ourselin S.
        • Gandini Wheeler-Kingshott C.A.
        • Chard D.
        • Thompson A.J.
        • Barkhof F.
        • Alexander D.C.
        • Ciccarelli O.
        Progression of regional grey matter atrophy in multiple sclerosis.
        Brain. 2018; 141: 1665-1677https://doi.org/10.1093/brain/awy088
        • Ewers M.
        • Cheng X.
        • Zhong Z.
        • Nural H.F.
        • Walsh C.
        • Meindl T.
        • Teipel S.J.
        • Buerger K.
        • He P.
        • Shen Y.
        • Hampel H.
        Increased CSF-BACE1 activity associated with decreased hippocampus volume in Alzheimer's Disease.
        J. Alzheimer's Dis. 2011; 25: 373-381https://doi.org/10.3233/JAD-2011-091153
        • Findlay J.A.
        • Hamilton D.L.
        • Ashford M.L.J.
        BACE1 activity impairs neuronal glucose oxidation: rescue by beta-hydroxybutyrate and lipoic acid.
        Front. Cell. Neurosci. 2015; 9https://doi.org/10.3389/fncel.2015.00382
        • Guix F.X.
        • Sartório C.L.
        • ILL-Raga G.
        BACE1 translation: at the crossroads between Alzheimer's Disease neurodegeneration and memory consolidation.
        J. Alzheimer's Dis. Reports. 2019; 3: 113-148https://doi.org/10.3233/ADR-180089
        • Hampel H.
        • Vassar R.
        • De Strooper B.
        • Hardy J.
        • Willem M.
        • Singh N.
        • Zhou J.
        • Yan R.
        • Vanmechelen E.
        • De Vos A.
        • Nisticò R.
        • Corbo M.
        • Imbimbo B.
        • Pietro, Streffer J.
        • Voytyuk I.
        • Timmers M.
        • Tahami Monfared A.A.
        • Irizarry M.
        • Albala B.
        • Koyama A.
        • Watanabe N.
        • Kimura T.
        • Yarenis L.
        • Lista S.
        • Kramer L.
        • Vergallo A.
        The β-Secretase BACE1 in Alzheimer's Disease.
        Biol. Psychiatry. 2021; 89: 745-756https://doi.org/10.1016/j.biopsych.2020.02.001
        • Hernandez-Mir G.
        • Raphael I.
        • Revu S.
        • Poholek C.H.
        • Avery L.
        • Hawse W.F.
        • Kane L.P.
        • McGeachy M.J.
        The Alzheimer's Disease–Associated Protein BACE1 Modulates T Cell Activation and Th17 Function.
        J. Immunol. 2019; 203: 665-675https://doi.org/10.4049/jimmunol.1800363
        • Hu X.
        • Hicks C.W.
        • He W.
        • Wong P.
        • Macklin W.B.
        • Trapp B.D.
        • Yan R.
        Bace1 modulates myelination in the central and peripheral nervous system.
        Nat. Neurosci. 2006; 9: 1520-1525https://doi.org/10.1038/nn1797
        • Kalb R.
        • Beier M.
        • Benedict R.H.
        • Charvet L.
        • Costello K.
        • Feinstein A.
        • Gingold J.
        • Goverover Y.
        • Halper J.
        • Harris C.
        • Kostich L.
        • Krupp L.
        • Lathi E.
        • LaRocca N.
        • Thrower B.
        • DeLuca J.
        Recommendations for cognitive screening and management in multiple sclerosis care.
        Mult. Scler. J. 2018; 24: 1665-1680https://doi.org/10.1177/1352458518803785
        • Krupp L.B.
        The Fatigue Severity Scale.
        Arch. Neurol. 1989; 46: 1121https://doi.org/10.1001/archneur.1989.00520460115022
        • Kuhn P.-H.
        • Marjaux E.
        • Imhof A.
        • De Strooper B.
        • Haass C.
        • Lichtenthaler S.F.
        Regulated Intramembrane Proteolysis of the Interleukin-1 Receptor II by α-, β-, and γ-Secretase.
        J. Biol. Chem. 2007; 282: 11982-11995https://doi.org/10.1074/jbc.M700356200
        • Mattsson N.
        • Axelsson M.
        • Haghighi S.
        • Malmeström C.
        • Wu G.
        • Anckarsäter R.
        • Sankaranarayanan S.
        • Andreasson U.
        • Fredrikson S.
        • Gundersen A.
        • Johnsen L.
        • Fladby T.
        • Tarkowski A.
        • Trysberg E.
        • Wallin A.
        • Anckarsäter H.
        • Lycke J.
        • Andersen O.
        • Simon A.
        • Blennow K.
        • Zetterberg H.
        Reduced cerebrospinal fluid BACE1 activity in multiple sclerosis.
        Mult. Scler. J. 2009; 15: 448-454https://doi.org/10.1177/1352458508100031
        • Millot P.
        • San C.
        • Bennana E.
        • Porte B.
        • Vignal N.
        • Hugon J.
        • Paquet C.
        • Hosten B.
        • Mouton-Liger F.
        STAT3 inhibition protects against neuroinflammation and BACE1 upregulation induced by systemic inflammation.
        Immunol. Lett. 2020; 228: 129-134https://doi.org/10.1016/j.imlet.2020.10.004
        • Mori F.
        • Rossi S.
        • Sancesario G.
        • Codecà C.
        • Mataluni G.
        • Monteleone F.
        • Buttari F.
        • Kusayanagi H.
        • Castelli M.
        • Motta C.
        • Studer V.
        • Bernardi G.
        • Koch G.
        • Bernardini S.
        • Centonze D.
        Cognitive and cortical plasticity deficits correlate with altered amyloid-β CSF levels in multiple sclerosis.
        Neuropsychopharmacology. 2011; 36: 559-568https://doi.org/10.1038/npp.2010.187
        • Mouton-Liger F.
        • Dumurgier J.
        • Cognat E.
        • Hourregue C.
        • Zetterberg H.
        • Vanderstichele H.
        • Vanmechelen E.
        • Bouaziz-Amar E.
        • Blennow K.
        • Hugon J.
        • Paquet C.
        CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer's disease.
        Alzheimers. Res. Ther. 2020; 12: 88https://doi.org/10.1186/s13195-020-00655-w
      1. Pedrabissi, L., & Santinello, M., 1989. Verifica della validità dello STAI forma Y di Spielberger [Verification of the validity of the STAI, Form Y, by Spielberger].

        • Petitfour J.
        • Ayrignac X.
        • Ginestet N.
        • Prin P.
        • Carra-Dallière C.
        • Hirtz C.
        • Charif M.
        • Lehmann S.
        • Labauge P.
        CSF β-amyloid is not a prognostic marker in multiple sclerosis patients.
        Mult. Scler. Relat. Disord. 2022; 68104096https://doi.org/10.1016/j.msard.2022.104096
        • Pietroboni A.M.
        • Caprioli M.
        • Carandini T.
        • Scarioni M.
        • Ghezzi L.
        • Arighi A.
        • Cioffi S.
        • Cinnante C.
        • Fenoglio C.
        • Oldoni E.
        • De Riz M.A.
        • Basilico P.
        • Fumagalli G.G.
        • Colombi A.
        • Giulietti G.
        • Serra L.
        • Triulzi F.
        • Bozzali M.
        • Scarpini E.
        • Galimberti D.
        CSF β-amyloid predicts prognosis in patients with multiple sclerosis.
        Mult. Scler. J. 2019; 25: 1223-1231https://doi.org/10.1177/1352458518791709
        • Pietroboni A.M.
        • Colombi A.
        • Carandini T.
        • Contarino V.E.
        • Ghezzi L.
        • Fumagalli G.G.
        • Arighi A.
        • Fenoglio C.
        • De Riz M.A.
        • Triulzi F.
        • Scarpini E.
        • Galimberti D.
        Low CSF β-amyloid levels predict early regional grey matter atrophy in multiple sclerosis.
        Mult. Scler. Relat. Disord. 2020; 39101899https://doi.org/10.1016/j.msard.2019.101899
        • Pravatà E.
        • Rocca M.A.
        • Valsasina P.
        • Riccitelli G.C.
        • Gobbi C.
        • Comi G.
        • Falini A.
        • Filippi M.
        Gray matter trophism, cognitive impairment, and depression in patients with multiple sclerosis.
        Mult. Scler. J. 2017; 23: 1864-1874https://doi.org/10.1177/1352458517692886
        • Qiao A.
        • Li J.
        • Hu Y.
        • Wang J.
        • Zhao Z.
        Reduction BACE1 expression via suppressing NF-κB mediated signaling by Tamibarotene in a mouse model of Alzheimer's disease. IBRO Neurosci.
        Reports. 2021; 10: 153-160https://doi.org/10.1016/j.ibneur.2021.02.004
        • Reiss A.B.
        • Arain H.A.
        • Stecker M.M.
        • Siegart N.M.
        • Kasselman L.J.
        Amyloid toxicity in Alzheimer's disease.
        Rev. Neurosci. 2018; 29: 613-627https://doi.org/10.1515/revneuro-2017-0063
      2. Sica, C., & Ghisi, M. (Nova S.P., 2007. The Italian versions of the Beck anxiety inventory and the beck depression inventory-II: psychometric properties and discriminant power.

        • Stampanoni Bassi M.
        • Garofalo S.
        • Marfia G.A.
        • Gilio L.
        • Simonelli I.
        • Finardi A.
        • Furlan R.
        • Sancesario G.M.
        • Di Giandomenico J.
        • Storto M.
        • Mori F.
        • Centonze D.
        • Iezzi E.
        Amyloid-β homeostasis bridges inflammation, synaptic plasticity deficits and cognitive dysfunction in multiple sclerosis.
        Front. Mol. Neurosci. 2017; 10https://doi.org/10.3389/fnmol.2017.00390
        • Stertz L.
        • Contreras-Shannon V.
        • Monroy-Jaramillo N.
        • Sun J.
        • Walss-Bass C.
        BACE1-deficient mice exhibit alterations in immune system pathways.
        Mol. Neurobiol. 2018; 55: 709-717https://doi.org/10.1007/s12035-016-0341-1
        • Sun J.
        • Zhang S.
        • Zhang Xiang
        • Zhang Xiaobao
        • Dong H.
        • Qian Y.
        IL-17A is implicated in lipopolysaccharide-induced neuroinflammation and cognitive impairment in aged rats via microglial activation.
        J. Neuroinflammation. 2015; 12: 165https://doi.org/10.1186/s12974-015-0394-5
        • Szabo L.
        • Eckert A.
        • Grimm A.
        Insights into disease-associated tau impact on mitochondria.
        Int. J. Mol. Sci. 2020; 21: 6344https://doi.org/10.3390/ijms21176344
        • The Goldman Consensus statement on depression in multiple sclerosis
        Mult. Scler. J. 2005; 11: 328-337https://doi.org/10.1191/1352458505ms1162oa
        • Timmers M.
        • Barão S.
        • Van Broeck B.
        • Tesseur I.
        • Slemmon J.
        • De Waepenaert K.
        • Bogert J.
        • Shaw L.M.
        • Engelborghs S.
        • Moechars D.
        • Mercken M.
        • Van Nueten L.
        • Tritsmans L.
        • de Strooper B.
        • Streffer J.R.
        BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants.
        J. Alzheimer's Dis. 2017; 56: 1437-1449https://doi.org/10.3233/JAD-160829
        • Virgilio E.
        • Vecchio D.
        • Crespi I.
        • Puricelli C.
        • Barbero P.
        • Galli G.
        • Cantello R.
        • Dianzani U.
        • Comi C.
        Cerebrospinal fluid biomarkers and cognitive functions at multiple sclerosis diagnosis.
        J. Neurol. 2022; 269: 3249-3257https://doi.org/10.1007/s00415-021-10945-4
        • Zhao J.
        • O'Connor T.
        • Vassar R.
        The contribution of activated astrocytes to Aβ production: Implications for Alzheimer's disease pathogenesis.
        J. Neuroinflammation. 2011; 8: 150https://doi.org/10.1186/1742-2094-8-150
        • Zheng Y.
        • Deng Y.
        • Gao J.
        • Lv C.
        • Lang L.
        • Shi J.
        • Yu C.
        • Gong Q.
        Icariside II inhibits lipopolysaccharide-induced inflammation and amyloid production in rat astrocytes by regulating IKK/IκB/NF-κB/BACE1 signaling pathway.
        Acta Pharmacol. Sin. 2020; 41: 154-162https://doi.org/10.1038/s41401-019-0300-2
        • Zhong Z.
        • Ewers M.
        • Teipel S.
        • Bürger K.
        • Wallin A.
        • Blennow K.
        • He P.
        • McAllister C.
        • Hampel H.
        • Shen Y.
        Levels of β-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment.
        Arch. Gen. Psychiatry. 2007; 64: 718https://doi.org/10.1001/archpsyc.64.6.718