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Các Đột Biến Cụ Thể Trong Vùng Liên Kết Cholesterol Ở APP Thay Đổi Quy Trình Xử Lý Của Nó Và Thúc Đẩy Sự Sản Xuất Các Peptit Aβ Ngắn Hơn, Ít Độc Hại Hơn
Tóm tắt
Cholesterol dư thừa trong não có liên quan mạnh mẽ đến sự phát triển của bệnh Alzheimer (AD). Trong nghiên cứu này, chúng tôi đánh giá sự hiện diện của vị trí liên kết cholesterol (CBS) trong các vùng xuyên màng và gần màng của protein tiền chất amyloid (APP) ảnh hưởng đến quá trình xử lý của nó như thế nào. Chúng tôi đã tạo ra chín đột biến điểm trong gen APP, thay đổi điện tích và/hoặc tính kỵ nước của các amino acid đã được chỉ ra là một phần của CBS trước đó. Hầu hết các đột biến đã kích thích sự giảm secretion của các peptide amyloid-β Aβ40 và Aβ42 từ các tế bào HEK293T được chuyển gen tạm thời. Chỉ có các đột biến ở vị trí 28 của Aβ trong chuỗi APP dẫn đến việc sản xuất đồng thời các peptide Aβ ngắn hơn tăng lên đáng kể. Phân tích khối phổ (MS) xác nhận sự chiếm ưu thế của Aβx-33 và Aβx-34 với đột biến APPK28A. Hoạt tính enzym của α-, β-, và γ-secretases vẫn không thay đổi trong các tế bào biểu hiện tất cả các đột biến. Tương tự, vị trí phụ trong tế bào của các đột biến trong các thể nội bào sớm không khác biệt so với protein APPWT. Một sự tăng tạm thời cholesterol màng tế bào đã làm gia tăng sản xuất Aβ40 và Aβ42 bởi APPWT, một hiệu ứng không có ở đột biến APPK28A. Cuối cùng, các peptide Aβ nguồn gốc từ WT nhưng không phải là đột biến CBS liên kết với các exosome giàu cholesterol. Tập hợp dữ liệu hiện tại đã chỉ ra vai trò lớn của các amino acid gần màng của CBS APP trong việc điều chỉnh sự sản xuất của các loại Aβ độc hại. Một cách tổng quát hơn, chúng làm rõ hơn vai trò của cholesterol trong sinh lý bệnh của AD.
Từ khóa
#Bệnh Alzheimer #cholesterol #protein tiền chất amyloid #peptide Aβ #đột biến genTài liệu tham khảo
Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608
De Strooper B, Annaert W (2010) Novel research horizons for presenilins and gamma-secretases in cell biology and disease. Annu Rev Cell Dev Biol 26:235–260
Shobab LA, Hsiung GY, Feldman HH (2005) Cholesterol in Alzheimer’s disease. Lancet Neurol 4:841–852
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90:1977–1981
Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci U S A 101:2070–2075
Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12:284–296
Lazar AN, Bich C, Panchal M, Desbenoit N, Petit VW, Touboul D, Dauphinot L, Marquer C, Laprevote O, Brunelle A, Duyckaerts C (2012) Time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging reveals cholesterol overload in the cerebral cortex of Alzheimer disease patients. Acta Neuropathol 125:133–144
Panchal M, Loeper J, Cossec JC, Perruchini C, Lazar A, Pompon D, Duyckaerts C (2010) Enrichment of cholesterol in microdissected Alzheimer’s disease senile plaques as assessed by mass spectrometry. J Lipid Res 51:598–605
Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, Sue LI, Woulfe J, Xu H, Stanimirovic DB, Zhang W (2008) Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and A beta production. Neurobiol Dis 29:422–437
Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ (2003) Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 100:11735–11740
Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A 95:6460–6464
Cossec JC, Marquer C, Panchal M, Lazar AN, Duyckaerts C, Potier MC (2010) Cholesterol changes in Alzheimer’s disease: methods of analysis and impact on the formation of enlarged endosomes. Biochim Biophys Acta 1801(8):839–845
Cossec JC, Simon A, Marquer C, Moldrich RX, Leterrier C, Rossier J, Duyckaerts C, Lenkei Z, Potier MC (2010) Clathrin-dependent APP endocytosis and Abeta secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim Biophys Acta 1801:846–852
Marquer C, Devauges V, Cossec JC, Liot G, Lecart S, Saudou F, Duyckaerts C, Leveque-Fort S, Potier MC (2011) Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. FASEB J 25:1295–1305
Marquer C, Laine J, Dauphinot L, Hanbouch L, Lemercier-Neuillet C, Pierrot N, Bossers K, Le M, Corlier F, Benstaali C, Saudou F, Thinakaran G, Cartier N, Octave JN, Duyckaerts C, Potier MC (2014) Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes. Mol Neurodegener 9:60
Grimm MO, Grimm HS, Tomic I, Beyreuther K, Hartmann T, Bergmann C (2008) Independent inhibition of Alzheimer disease beta- and gamma-secretase cleavage by lowered cholesterol levels. J Biol Chem 283:11302–11311
Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ (2008) Direct and potent regulation of gamma-secretase by its lipid microenvironment. J Biol Chem 283:22529–22540
Pierrot N, Tyteca D, D’Auria L, Dewachter I, Gailly P, Hendrickx A, Tasiaux B, Haylani LE, Muls N, N’Kuli F, Laquerriere A, Demoulin JB, Campion D, Brion JP, Courtoy PJ, Kienlen-Campard P, Octave JN (2013) Amyloid precursor protein controls cholesterol turnover needed for neuronal activity. EMBO Mol Med 5:608–625
Di Scala C, Chahinian H, Yahi N, Garmy N, Fantini J (2014) Interaction of Alzheimer’s beta-amyloid peptides with cholesterol: mechanistic insights into amyloid pore formation. Biochemistry 53:4489–4502
Fantini J, Yahi N, Garmy N (2013) Cholesterol accelerates the binding of Alzheimer’s beta-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation. Front Physiol 4:120
Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR (2012) The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336:1168–1171
Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry 47:9428–9446
Beel AJ, Sakakura M, Barrett PJ, Sanders CR (2012) Direct binding of cholesterol to the amyloid precursor protein: an important interaction in lipid-Alzheimer’s disease relationships? Biochim Biophys Acta 1801(8):975–982
Nierzwicki L, Czub J (2015) Specific binding of cholesterol to the amyloid precursor protein: structure of the complex and driving forces characterized in molecular detail. J Phys Chem Lett 6:784–790
Perrin F, Papadopoulos N, Suelves N, Opsomer R, Vadukul DM, Vrancx C, Smith SO, Vertommen D, Kienlen-Campard P, Constantinescu SN (2020) Dimeric transmembrane orientations of APP/C99 regulate gamma-secretase processing line impacting signaling and oligomerization. iScience 23:101887
Moore BD, Martin J, de Mena L, Sanchez J, Cruz PE, Ceballos-Diaz C, Ladd TB, Ran Y, Levites Y, Kukar TL, Kurian JJ, McKenna R, Koo EH, Borchelt DR, Janus C, Rincon-Limas D, Fernandez-Funez P, Golde TE (2018) Short Abeta peptides attenuate Abeta42 toxicity in vivo. J Exp Med 215:283–301
Vandersteen A, Hubin E, Sarroukh R, De Baets G, Schymkowitz J, Rousseau F, Subramaniam V, Raussens V, Wenschuh H, Wildemann D, Broersen K (2012) A comparative analysis of the aggregation behavior of amyloid-beta peptide variants. FEBS Lett 586:4088–4093
Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat Med 3:1016–1020
Abdullah M, Nakamura T, Ferdous T, Gao Y, Chen Y, Zou K, Michikawa M (2021) Cholesterol regulates exosome release in cultured astrocytes. Front Immunol 12:722581
Skotland T, Hessvik NP, Sandvig K, Llorente A (2019) Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology. J Lipid Res 60:9–18
Kienlen-Campard P, Tasiaux B, Van Hees J, Li M, Huysseune S, Sato T, Fei JZ, Aimoto S, Courtoy PJ, Smith SO, Constantinescu SN, Octave JN (2008) Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs. J Biol Chem 283:7733–7744
Liu L, Lauro BM, Wolfe MS, Selkoe DJ (2021) Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate gamma-secretase function in generating Alzheimer-causing Abeta peptides. J Biol Chem 296:100393
Panahi A, Bandara A, Pantelopulos GA, Dominguez L, Straub JE (2016) Specific binding of cholesterol to C99 domain of amyloid precursor protein depends critically on charge state of protein. J Phys Chem Lett 7:3535–3541
Bugiani O, Giaccone G, Rossi G, Mangieri M, Capobianco R, Morbin M, Mazzoleni G, Cupidi C, Marcon G, Giovagnoli A, Bizzi A, Di Fede G, Puoti G, Carella F, Salmaggi A, Romorini A, Patruno GM, Magoni M, Padovani A, Tagliavini F (2010) Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP. Arch Neurol 67:987–995
Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J (2000) Substitutions at codon 22 of Alzheimer’s abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem 275:27110–27116
Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H (2008) A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann Neurol 63:377–387
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 4:887–893
van der Kant R, Langness VF, Herrera CM, Williams DA, Fong LK, Leestemaker Y, Steenvoorden E, Rynearson KD, Brouwers JF, Helms JB, Ovaa H, Giera M, Wagner SL, Bang AG, Goldstein LSB (2019) Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-beta in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24(363–375):e369
Nicastro MC, Spigolon D, Librizzi F, Moran O, Ortore MG, Bulone D, Biagio PL, Carrotta R (2016) Amyloid beta-peptide insertion in liposomes containing GM1-cholesterol domains. Biophys Chem 208:9–16
Steck TL, Lange Y (2018) Transverse distribution of plasma membrane bilayer cholesterol: picking sides. Traffic 19:750–760
Murate M, Kobayashi T (2016) Revisiting transbilayer distribution of lipids in the plasma membrane. Chem Phys Lipids 194:58–71
Rivel T, Ramseyer C, Yesylevskyy S (2019) The asymmetry of plasma membranes and their cholesterol content influence the uptake of cisplatin. Sci Rep 9:5627
Ren Z, Schenk D, Basi GS, Shapiro IP (2007) Amyloid beta-protein precursor juxtamembrane domain regulates specificity of gamma-secretase-dependent cleavages. J Biol Chem 282:35350–35360
Kukar TL, Ladd TB, Robertson P, Pintchovski SA, Moore B, Bann MA, Ren Z, Jansen-West K, Malphrus K, Eggert S, Maruyama H, Cottrell BA, Das P, Basi GS, Koo EH, Golde TE (2011) Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid beta peptide length: support for a sequential model of gamma-secretase intramembrane proteolysis and regulation by the amyloid beta precursor protein (APP) juxtamembraneregion. J Biol Chem 286:39804–39812
Ousson S, Saric A, Baguet A, Losberger C, Genoud S, Vilbois F, Permanne B, Hussain I, Beher D (2013) Substrate determinants in the C99 juxtamembranedomains differentially affect gamma-secretase cleavage specificity and modulator pharmacology. J Neurochem 125:610–619
Devkota S, Williams TD, Wolfe MS (2021) Familial Alzheimer’s disease mutations in amyloid protein precursor alter proteolysis by gamma-secretase to increase amyloid beta-peptides of >/=45 residues. J Biol Chem 296:100281
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y (2019) Recognition of the amyloid precursor protein by human gamma-secretase. Science 363(6428):eaaw0930
Tarus B, Straub JE, Thirumalai D (2008) Structures and free-energy landscapes of the wild type and mutants of the Abeta(21–30) peptide are determined by an interplay between intrapeptide electrostatic and hydrophobic interactions. J Mol Biol 379:815–829
Sambasivam D, Sivanesan S, Ashok BS, Rajadas J (2011) Structural preferences of Abeta fragments in different micellar environments. Neuropeptides 45:369–376
Shuaib S, Saini RK, Goyal D, Goyal B (2020) Impact of K16A and K28A mutation on the structure and dynamics of amyloid-beta42 peptide in Alzheimer’s disease: key insights from molecular dynamics simulations. J Biomol Struct Dyn 38:708–721
Yang Y, Arseni D, Zhang W, Huang M, Lovestam S, Schweighauser M, Kotecha A, Murzin AG, Peak-Chew SY, Macdonald J, Lavenir I, Garringer HJ, Gelpi E, Newell KL, Kovacs GG, Vidal R, Ghetti B, Ryskeldi-Falcon B, Scheres SHW, Goedert M (2022) Cryo-EM structures of amyloid-beta 42 filaments from human brains. Science 375:167–172
Fluhrer R, Multhaup G, Schlicksupp A, Okochi M, Takeda M, Lammich S, Willem M, Westmeyer G, Bode W, Walter J, Haass C (2003) Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. J Biol Chem 278:5531–5538
Shi XP, Tugusheva K, Bruce JE, Lucka A, Wu GX, Chen-Dodson E, Price E, Li Y, Xu M, Huang Q, Sardana MK, Hazuda DJ (2003) Beta-secretase cleavage at amino acid residue 34 in the amyloid beta peptide is dependent upon gamma-secretase activity. J Biol Chem 278:21286–21294
Caillava C, Ranaldi S, Lauritzen I, Bauer C, Fareh J, Abraham JD, Checler F (2014) Study on Abeta34 biology and detection in transgenic mice brains. Neurobiol Aging 35:1570–1581
Akerman SC, Hossain S, Shobo A, Zhong Y, Jourdain R, Hancock MA, George K, Breton L, Multhaup G (2019) Neurodegenerative disease-related proteins within the epidermal layer of the human skin. J Alzheimers Dis 69:463–478
Kirabali T, Rigotti S, Siccoli A, Liebsch F, Shobo A, Hock C, Nitsch RM, Multhaup G, Kulic L (2019) The amyloid-beta degradation intermediate Abeta34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer’s disease. Acta Neuropathol Commun 7:194
Liebsch F, Kulic L, Teunissen C, Shobo A, Ulku I, Engelschalt V, Hancock MA, van der Flier WM, Kunach P, Rosa-Neto P, Scheltens P, Poirier J, Saftig P, Bateman RJ, Breitner J, Hock C, Multhaup G (2019) Abeta34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression. Nat Commun 10:2240
Hernandez-Guillamon M, Mawhirt S, Blais S, Montaner J, Neubert TA, Rostagno A, Ghiso J (2015) Sequential amyloid-beta degradation by the matrix metalloproteases MMP-2 and MMP-9. J Biol Chem 290:15078–15091
Dawkins E, Small DH (2014) Insights into the physiological function of the beta-amyloid precursor protein: beyond Alzheimer’s disease. J Neurochem 129:756–769
Wilhelm BG, Mandad S, Truckenbrodt S, Krohnert K, Schafer C, Rammner B, Koo SJ, Classen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO (2014) Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344:1023–1028
Samant NP, Gupta GL (2020) Novel therapeutic strategies for Alzheimer’s disease targeting brain cholesterol homeostasis. Eur J Neurosci 53(2):673–686
Hudry E, Van Dam D, Kulik W, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P, Cartier N (2010) Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer’s disease. Mol Ther 18:44–53
Lopez-Gambero AJ, Sanjuan C, Serrano-Castro PJ, Suarez J, Rodriguez de Fonseca F (2020) The biomedical uses of inositols: a nutraceutical approach to metabolic dysfunction in aging and neurodegenerative diseases. Biomedicines 8(9):295
Sinha S, Du Z, Maiti P, Klarner FG, Schrader T, Wang C, Bitan G (2012) Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. ACS Chem Neurosci 3:451–458
Sinha S, Lopes DH, Bitan G (2012) A key role for lysine residues in amyloid beta-protein folding, assembly, and toxicity. ACS Chem Neurosci 3:473–481
Portelius E, Tran AJ, Andreasson U, Persson R, Brinkmalm G, Zetterberg H, Blennow K, Westman-Brinkmalm A (2007) Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 6:4433–4439
Brinkmalm G, Portelius E, Ohrfelt A, Mattsson N, Persson R, Gustavsson MK, Vite CH, Gobom J, Mansson JE, Nilsson J, Halim A, Larson G, Ruetschi U, Zetterberg H, Blennow K, Brinkmalm A (2012) An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid beta and amyloid precursor protein in human and cat cerebrospinal fluid. J Mass Spectrom 47:591–603
Gkanatsiou E, Portelius E, Toomey CE, Blennow K, Zetterberg H, Lashley T, Brinkmalm G (2019) A distinct brain beta amyloid signature in cerebral amyloid angiopathy compared to Alzheimer’s disease. Neurosci Lett 701:125–131