Amyloid β42 (Aβ42) plays a decisive role in the pathology of Alzheimer's disease. The Aβ42 peptide can aggregate into various supramolecular structures, with oligomers being the most toxic form. However, different Aβ species that cause different effects have been described. Many cell death pathways can be activated in connection with Aβ action, including apoptosis, necroptosis, pyroptosis, oxidative stress, ferroptosis, alterations in mitophagy, autophagy, and endo/lysosomal functions. In this study, we used a model of differentiated SH-SY5Y cells and applied two different Aβ42 preparations for 2 and 4 days. Although we found no difference in the shape and size of Aβ species prepared by two different methods (NaOH or NH4OH for Aβ solubilization), we observed strong differences in their effects. Treatment of cells with NaOH-Aβ42 mainly resulted in damage of mitochondrial function and increased production of reactive oxygen species, whereas application of NH4OH-Aβ42 induced necroptosis and first steps of apoptosis, but also caused an increase in protective Hsp27. Moreover, the two Aβ42 preparations differed in the mechanism of interaction with the cells, with the effect of NaOH-Aβ42 being dependent on monosialotetrahexosylganglioside (GM1) content, whereas the effect of NH4OH-Aβ42 was independent of GM1. This suggests that, although both preparations were similar in size, minor differences in secondary/tertiary structure are likely to strongly influence the resulting processes. Our work reveals, at least in part, one of the possible causes of the inconsistency in the data observed in different studies on Aβ-toxicity pathways.

Department of Physiology Faculty of Sciences Charles University Viničná 7 12844 Prague 2 Czech Republic

Institute of Physics Faculty of Mathematics and Physics Charles University Ke Karlovu 5 12116 Prague 2 Czech Republic

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Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal cell death. Physiol Rev. 2018;98:813–80. PubMed PMC

Chafekar SM, Hoozemans JJ, Zwart R, Baas F, Scheper W. Abeta 1–42 induces mild endoplasmic reticulum stress in an aggregation state-dependent manner. Antioxid Redox Signal. 2007;9:2245–54. PubMed

Resende R, Ferreiro E, Pereira C, De Oliveira CR. Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1–42: Involvement of endoplasmic reticulum calcium release in oligomer-induced cell death. Neuroscience. 2008;155:725–37. PubMed

Picone P, Carrotta R, Montana G, Nobile MR, Biagio PLS, Di Carlo M. Aβ oligomers and fibrillar aggregates induce different apoptotic pathways in LAN5 neuroblastoma cell cultures. Biophys J. 2009;96:4200–11. PubMed PMC

Bucciantini M, Rigacci S, Stefani M. Amyloid aggregation: role of biological membranes and the aggregate-membrane system. J Phys Chem Lett. 2014;5:517–27. PubMed

Jekabsone A, Jankeviciute S, Pampuscenko K, Borutaite V, Morkuniene R. The role of intracellular Ca and mitochondrial ROS in small Aβ oligomer-induced microglial death. Int J Mol Sci. 2023;24:12315. PubMed PMC

Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Aβ are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998;95:6448–53. PubMed PMC

Yamamoto N, Matsubara E, Maeda S, Minagawa H, Takashima A, Maruyama W, et al. A ganglioside-induced toxic soluble Aβ assembly -: its enhanced formation from Aβ bearing the arctic mutation. J Biol Chem. 2007;282:2646–55. PubMed

Bernstein SL, Dupuis NF, Lazo ND, Wyttenbach T, Condron MM, Bitan G, et al. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat Chem. 2009;1:326–31. PubMed PMC

Williams TL, Johnson BR, Urbanc B, Jenkins AT, Connell SD, Serpell LC. Abeta42 oligomers, but not fibrils, simultaneously bind to and cause damage to ganglioside-containing lipid membranes. Biochem J. 2011;439:67–77. PubMed

Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-β oligomer hypothesis: beginning of the third decade. J Alzheimers Dis. 2018;64:S567–610. PubMed PMC

Ewald M, Henry S, Lambert E, Feuillie C, Bobo C, Cullin C, et al. High speed atomic force microscopy to investigate the interactions between toxic A peptides and model membranes in real time: impact of the membrane composition. Nanoscale. 2019;11:7229–38. PubMed

Xue C, Tran J, Wang HS, Park G, Hsu F, Guo ZF. Aβ42 fibril formation from predominantly oligomeric samples suggests a link between oligomer heterogeneity and fibril polymorphism. R Soc Open Sci. 2019;6: 190179. PubMed PMC

Cizas P, Budvytyte R, Morkuniene R, Moldovan R, Broccio M, Lösche M, et al. Size-dependent neurotoxicity of β-amyloid oligomers. Arch Biochem Biophys. 2010;496:84–92. PubMed PMC

Hartley DM, Walsh DM, Ye CPP, Diehl T, Vasquez S, Vassilev PM, et al. Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999;19:8876–84. PubMed PMC

Takada E, Okubo K, Yano Y, Iida K, Someda M, Hirasawa A, et al. Molecular mechanism of apoptosis by amyloid β-Protein fibrils formed on neuronal cells. ACS Chem Neurosci. 2020;11:796–805. PubMed

Yuyama K, Yanagisawa K. Sphingomyelin accumulation provides a favorable milieu for GM1 ganglioside-induced assembly of amyloid beta-protein. Neurosci Lett. 2010;481:168–72. PubMed

Viola KL, Klein WL. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 2015;129:183–206. PubMed PMC

Evangelisti E, Cascella R, Becatti M, Marrazza G, Dobson CM, Chiti F, et al. Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases. Sci Rep UK. 2016;6:32721. PubMed PMC

Fernández-Pérez EJ, Sepúlveda FJ, Peoples R, Aguayo LG. Role of membrane GM1 on early neuronal membrane actions of Aβ during onset of Alzheimer’s disease. BBA Mol Basis Dis. 2017;1863:3105–16. PubMed

Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017;38:1205–35. PubMed PMC

Rudajev V, Novotny J. The role of lipid environment in ganglioside GM1-induced amyloid β aggregation. Membranes-Basel. 2020;10:226. PubMed PMC

Rudajev V, Novotny J. Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease. Front Mol Neurosci. 2022;15: 937056. PubMed PMC

Orrenius S, Gogvadze A, Zhivotovsky B. Mitochondrial oxidative stress: Implications for cell death. Annu Rev Pharmacol. 2007;7:143–83. PubMed

Vanden Berghe T, Kaiser WJ, Bertrand MJM, Vandenabeele P. Molecular crosstalk between apoptosis, necroptosis, and survival signaling. Mol Cell Oncol. 2015;2: e975093. PubMed PMC

Choi SB, Kwon S, Kim JH, Ahn NH, Lee JH, Yang SH. The molecular mechanisms of neuroinflammation in Alzheimer’s disease, the consequence of neural cell death. Int J Mol Sci. 2023;24:11757. PubMed PMC

Wu HJ, Che XR, Zheng QL, Wu A, Pan K, Shao AW, et al. Caspases: a molecular switch node in the crosstalk between autophagy and apoptosis. Int J Biol Sci. 2014;10:1072–83. PubMed PMC

Paradis E, Douillard H, Koutroumanis M, Goodyer C, LeBlanc A. Amyloid beta peptide of Alzheimer’s disease downregulates bcl-2 and upregulates bax expression in human neurons. J Neurosci. 1996;16:7533–9. PubMed PMC

Su JH, Deng GM, Cotman CW. Bax protein expression is increased in Alzheimer’s brain: Correlations with DNA damage, Bcl-2 expression, and brain pathology. J Neuropath Exp Neur. 1997;56:86–93. PubMed

Selznick LA, Zheng TS, Flavell RA, Rakic P, Roth KA. Amyloid beta-induced neuronal death is bax-dependent but caspase-independent. J Neuropath Exp Neur. 2000;59:271–9. PubMed

Dewson G, Kluck RM. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J Cell Sci. 2009;122:2801–8. PubMed PMC

Kudo W, Lee HP, Smith MA, Zhu X, Matsuyama S, Lee HG. Inhibition of Bax protects neuronal cells from oligomeric Aβ neurotoxicity. Cell Death Dis. 2012;3: e309. PubMed PMC

Zhao Y, Zhao BL. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev. 2013;2013: 316523. PubMed PMC

Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018;14:450–64. PubMed PMC

Peña-Bautista C, Vigor C, Galano JM, Oger C, Durand T, Ferrer I, et al. Plasma lipid peroxidation biomarkers for early and non-invasive Alzheimer disease detection. Free Radical Bio Med. 2018;124:388–94. PubMed

Park MW, Cha HW, Kim J, Kim JH, Yang H, Yoon S, et al. NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases. Redox Biol. 2021;41: 101947. PubMed PMC

Baruah P, Moorthy H, Ramesh M, Padhi D, Govindaraju T. A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer’s disease. Chem Sci. 2023;14:9427–38. PubMed PMC

Zhao D, Yang KL, Guo H, Zeng JS, Wang SS, Xu H, et al. Mechanisms of ferroptosis in Alzheimer’s disease and therapeutic effects of natural plant products: a review. Biomed Pharmacother. 2023;164: 114312. PubMed

Zhang JJ, Zhang RF, Meng XK. Protective effect of pyrroloquinoline quinone against Aβ-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosci Lett. 2009;464:165–9. PubMed

Ding HT, Wang HT, Zhao YX, Sun DK, Zhai X. Protective effects of baicalin on aβ-induced learning and memory deficit, oxidative stress, and apoptosis in rat. Cell Mol Neurobiol. 2015;35:623–32. PubMed PMC

Oguchi T, Ono R, Tsuji M, Shozawa H, Somei M, Inagaki M, et al. Cilostazol suppresses Aβ-induced Neurotoxicity in SH-SY5Y cells through inhibition of oxidative stress and MAPK signaling pathway. Front Aging Neurosci. 2017;9:337. PubMed PMC

Butterfield DA, Boyd-Kimball D. Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer’s disease. J Alzheimers Dis. 2018;62:1345–67. PubMed PMC

Cinar R, Naziroglu M. TRPM2 channel inhibition attenuates amyloid β42-induced apoptosis and oxidative stress in the hippocampus of mice. Cell Mol Neurobiol. 2023;43:1335–53. PubMed PMC

Zhang GH, Chin KL, Yan SY, Pare R. Antioxioxidant and antiapoptotic effects of thymosin β4 in Aβ-induced SH-SY5Y cells via the 5-HTR1A/ERK axis. PLoS ONE. 2023;18: e0287817. PubMed PMC

Chen X, Li W, Ren J, Huang D, He WT, Song Y, et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 2014;24:105–21. PubMed PMC

Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, et al. Necroptosis activation in Alzheimer’s disease. Nat Neurosci. 2017;20:1236–46. PubMed

Mompeán M, Li WB, Li JX, Laage S, Siemer AB, Bozkurt G, et al. The structure of the necrosome RIPK1-RIPK3 core, a human hetero-amyloid signaling complex. Cell. 2018;173:1244–53. PubMed PMC

Li S, Qu LL, Wang XB, Kong LY. Novel insights into RIPK1 as a promising target for future Alzheimer’s disease treatment. Pharmacol Therapeut. 2022;231: 107979. PubMed

Bai YL, Liu D, Zhang HH, Wang YY, Wang DG, Cai HB, et al. N-salicyloyl tryptamine derivatives as potential therapeutic agents for Alzheimer’s disease with neuroprotective effects. Bioorg Chem. 2021;115: 105255. PubMed

Huang YH, Li XY, Luo GF, Wang JL, Li RH, Zhou CY, et al. Pyroptosis as a candidate therapeutic target for Alzheimer’s disease. Front Aging Neurosci. 2022;14: 996646. PubMed PMC

Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022;25:688–701. PubMed PMC

Zaretsky DV, Zaretskaia MV, Molkov YI. Membrane channel hypothesis of lysosomal permeabilization by beta-amyloid. Neurosci Lett. 2022;770: 136338. PubMed

Lipinski MM, Zheng B, Lu T, Yan ZY, Py BF, Ng A, et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc Natl Acad Sci USA. 2010;107:14164–9. PubMed PMC

Wang HM, Ma JF, Tan YY, Wang ZQ, Sheng CY, Chen SD, et al. Amyloid-β induces reactive oxygen species-mediated autophagic cell death in U87 and SH-SY5Y Cells. J Alzheimers Dis. 2010;21:597–610. PubMed

Saleem S, Biswas SC. Tribbles pseudokinase 3 induces both apoptosis and autophagy in amyloid-beta-induced neuronal death. J Biol Chem. 2017;292:2571–85. PubMed PMC

Fang EF, Hou YJ, Palikaras K, Adriaanse BA, Kerr JS, Yang BM, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci. 2019;22:401–12. PubMed PMC

Wang W, Gu X, Cheng Z, Lu X, Xie S, Liu X. IKKbeta alleviates neuron injury in Alzheimer’s disease via regulating autophagy and RIPK1-mediated necroptosis. Mol Neurobiol. 2022;59:2407–23. PubMed

Bassik MC, Scorrano L, Oakes SA, Pozzan T, Korsmeyer SJ. Phosphorylation of BCL-2 regulates ER Ca homeostasis and apoptosis. EMBO J. 2004;23:1207–16. PubMed PMC

Wei Y, Sinha S, Levine B. Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy. 2008;4:949–51. PubMed PMC

Wirawan E, Vande Walle L, Kersse K, Cornelis S, Claerhout S, Vanoverberghe I, et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 2010;1: e18. PubMed PMC

Rubinstein AD, Kimchi A. Life in the balance - a mechanistic view of the crosstalk between autophagy and apoptosis. J Cell Sci. 2012;125:5259–68. PubMed

Charan RA, Johnson BN, Zaganelli S, Nardozzi JD, LaVoie MJ. Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin. Cell Death Dis. 2014;5: e1313. PubMed PMC

Saleem S. Apoptosis, autophagy, necrosis and their multi galore crosstalk in neurodegeneration. Neuroscience. 2021;469:162–74. PubMed

Gurung P, Anand PK, Malireddi RKS, Walle LV, Van Opdenbosch N, Dillon CP, et al. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J Immunol. 2014;192:1835–46. PubMed PMC

Orozco S, Yatim N, Werner MR, Tran H, Gunja SY, Tait SWG, et al. RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ. 2014;21:1511–21. PubMed PMC

Henry CM, Martin SJ. Caspase-8 acts in a non-enzymatic role as a scaffold for assembly of a pro-inflammatory “FADDosome’’ complex upon TRAIL Stimulation. Mol Cell. 2017;65:715–29. PubMed

Kumar S, Budhathoki S, Oliveira CB, Kahle AD, Calhan OY, Lukens JR, et al. Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation. JCI Insight. 2023;8: e157433. PubMed PMC

Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem. 2005;280:17294–300. PubMed

Calvo-Rodriguez M, Hernando-Perez E, Nuñez L, Villalobos C. Amyloid β oligomers increase ER-mitochondria ca cross talk in young hippocampal neurons and exacerbate aging-induced intracellular Ca remodeling. Front Cell Neurosci. 2019;13:22. PubMed PMC

Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Bio. 2007;8:741–52. PubMed

Ku B, Woo JS, Liang C, Lee KH, Jung JU, Oh BH. An insight into the mechanistic role of Beclin 1 and its inhibition by prosurvival Bcl-2 family proteins. Autophagy. 2008;4:519–20. PubMed

Naderi S, Khodagholi F, Pourbadie HG, Naderi N, Rafiei S, Janahmadi M, et al. Role of amyloid beta (25–35) neurotoxicity in the ferroptosis and necroptosis as modalities of regulated cell death in Alzheimer’s disease. Neurotoxicology. 2023;94:71–86. PubMed

Ciccotosto GD, Tew DJ, Drew SC, Smith DG, Johanssen T, Lal V, et al. Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity. Neurobiol Aging. 2011;32:235–48. PubMed

Ryan TM, Caine J, Mertens HDT, Kirby N, Nigro J, Breheney K, et al. Ammonium hydroxide treatment of Aβ produces an aggregate free solution suitable for biophysical and cell culture characterization. PeerJ. 2013;1: e73. PubMed PMC

Geng LJ, Liu W, Chen Y. Tanshinone IIA attenuates Aβ-induced neurotoxicity by down-regulating COX-2 expression and PGE2 synthesis via inactivation of NF-κB pathway in SH-SY5Y cells. J Biol Res-Thessalon. 2019;26:15. PubMed PMC

Krishtal J, Metsla K, Bragina O, Tougu V, Palumaa P. Toxicity of amyloid-β peptides varies depending on differentiation route of SH-SY5Y cells. J Alzheimers Dis. 2019;71:879–87. PubMed

El Kirat K, Burton I, Dupres V, Dufrene YF. Sample preparation procedures for biological atomic force microscopy. J Microsc-Oxford. 2005;218:199–207. PubMed

Deegan RD, Bakajin O, Dupont TF, Huber G, Nagel SR, Witten TA. Capillary flow as the cause of ring stains from dried liquid drops. Nature. 1997;389:827–9.

Kopecky V, Baumruk V. Structure of the ring in drop coating deposited proteins and its implication for Raman spectroscopy of biomolecules. Vib Spectrosc. 2006;42:184–7.

Deegan RD. Pattern formation in drying drops. Phys Rev E. 2000;61:475–85. PubMed

Stockert JC, Blázquez-Castro A, Cañete M, Horobin RW, Villanueva A. MTT assay for cell viability: Intracellular localization of the formazan product is in lipid droplets. Acta Histochem. 2012;114:785–96. PubMed

Ozdemir AY, Akbay E, Onur MA. Comparison of the different isoforms of vitamin e against amyloid beta-induced neurodegeneration. Turk J Biol. 2022;46:388–99. PubMed PMC

Kamiloglu S, Sari G, Ozdal T, Capanoglu E. Guidelines for cell viability assays. Food Front. 2020;1:332–49.

Thammasart S, Namchaiw P, Pasuwat K, Tonsomboon K, Khantachawana A. Attenuation Abeta1-42-induced neurotoxicity in neuronal cell by 660nm and 810nm LED light irradiation. PLoS ONE. 2023;18: e0283976. PubMed PMC

Mali AS, Honc O, Hejnova L, Novotny J. Opioids alleviate oxidative stress via the Nrf2/HO-1 pathway in LPS-stimulated microglia. Int J Mol Sci. 2023;24:11089. PubMed PMC

De Leon JAD, Borges CR. Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. Jove-J Vis Exp. 2020;1:61122. PubMed PMC

Presley AD, Fuller KM, Arriaga EA. MitoTracker green labeling of mitochondrial proteins and their subsequent analysis by capillary electrophoresis with laser-induced fluorescence detection. J Chromatogr B. 2003;793:141–50. PubMed

Monteiro LD, Davanzo GG, de Aguiar CF, Moraes-Vieira PMM. Using flow cytometry for mitochondrial assays. MethodsX. 2020;7: 100938. PubMed PMC

Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356:513–9. PubMed PMC

Honc O, Novotny J. Methadone potentiates the cytotoxicity of temozolomide by impairing calcium homeostasis and dysregulation of PARP in glioblastoma cells. Cancers. 2023;15:3567. PubMed PMC

Ng KB, Bustamam A, Sukari MA, Abdelwahab SI, Mohan S, Buckle MJC, et al. Induction of selective cytotoxicity and apoptosis in human T4-lymphoblastoid cell line (CEMss) by boesenbergin a isolated from rhizomes involves mitochondrial pathway, activation of caspase 3 and G2/M phase cell cycle arrest. BMC Complem Altern M. 2013;13:41. PubMed PMC

Salim LZA, Mohan S, Othman R, Abdelwahab SI, Kamalidehghan B, Sheikh BY, et al. Thymoquinone induces mitochondria-mediated apoptosis in acute lymphoblastic leukaemia. Molecules. 2013;18:11219–40. PubMed PMC

Bagheri E, Hajiaghaalipour F, Nyamathulla S, Salehen NA. Ethanolic extract of inhibit proliferation of HCT-116 colon cancer cells caspase activation. RSC Adv. 2018;8:681–9. PubMed PMC

Martin RM, Leonhardt H, Cardoso MC. DNA labeling in living cells. Cytom Part A. 2005;67:45–52. PubMed

Hu XM, Li ZX, Lin RH, Shan JQ, Yu QW, Wang RX, et al. Guidelines for regulated cell death assays: a systematic summary, a categorical comparison. Prospect Front Cell Dev Biol. 2021;9: 634690. PubMed PMC

Cao Y, Fan MY, Pei YF, Su L, Xiao WW, Chen F, et al. CCAAT/enhancer-binding protein homologous protein (CHOP) deficiency attenuates heatstroke-induced intestinal injury. Inflammation. 2022;45:695–711. PubMed PMC

Cockova Z, Honc O, Telensky P, Olsen MJ, Novotny J. Streptozotocin-induced astrocyte mitochondrial dysfunction is ameliorated by FTO inhibitor MO-I-500. ACS Chem Neurosci. 2021;12:3818–28. PubMed

Lin YC, Komatsu H, Ma J, Axelsen PH, Fakhraai Z. Identifying polymorphs of amyloid-beta (1–40) fibrils using high-resolution atomic force microscopy. J Phys Chem B. 2019;123:10376–83. PubMed

Forster JI, Köglsberger S, Trefois C, Boyd O, Baumuratov AS, Buck L, et al. Characterization of differentiated sh-sy5y as neuronal screening model reveals increased oxidative vulnerability. J Biomol Screen. 2016;21:496–509. PubMed PMC

Krishtal J, Bragina O, Metsla K, Palumaa P, Tougu V. In situ fibrillizing amyloid- beta 1–42 induces neurite degeneration and apoptosis of differentiated SH-SY5Y cells. PLoS ONE. 2017;12: e0186636. PubMed PMC

Lopez-Suarez L, Al Awabdh S, Coumoul X, Chauvet C. The SH-SY5Y human neuroblastoma cell line, a relevant in vitro cell model for investigating neurotoxicology in human: Focus on organic pollutants. Neurotoxicology. 2022;92:131–55. PubMed

Qian YH, Xiao QL, Xu J. The protective effects of tanshinone IIA on β-amyloid protein (1–42)-induced cytotoxicity via activation of the Bcl-xL pathway in neuron. Brain Res Bull. 2012;88:354–8. PubMed

Yang SH, Lee DK, Shin J, Lee S, Baek S, Kim J, et al. Nec-1 alleviates cognitive impairment with reduction of Abeta and tau abnormalities in APP/PS1 mice. EMBO Mol Med. 2017;9:61–77. PubMed PMC

Liu WY, Li Y, Li Y, Xu LZ, Jia JP. Carnosic acid attenuates AβOs-induced apoptosis and synaptic impairment via regulating NMDAR2B and its downstream cascades in SH-SY5Y cells. Mol Neurobiol. 2023;60:133–44. PubMed

Xu SC, Zhong M, Zhang L, Wang Y, Zhou Z, Hao YT, et al. Overexpression of Tfam protects mitochondria against β-amyloid-induced oxidative damage in SH-SY5Y cells. FEBS J. 2009;276:4224–33. PubMed

Du YL, Yang DH, Li L, Luo GR, Li T, Fan XL, et al. An insight into the mechanistic role of p53-mediated autophagy induction in response to proteasomal inhibition-induced neurotoxicity. Autophagy. 2009;5:663–75. PubMed

Radi E, Formichi P, Battisti C, Federico A. Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis. 2014;42:S125–52. PubMed

Zhu ZH, Reiser G. The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases. Neurochem Int. 2018;115:69–79. PubMed

Okle O, Stemmer K, Deschl U, Dietrich DR. BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations. Toxicol Sci. 2013;131:217–24. PubMed

Wongprayoon P, Govitrapong P. Melatonin protects SH-SY5Y neuronal cells against methamphetamine-induced endoplasmic reticulum stress and apoptotic cell death. Neurotox Res. 2017;31:1–10. PubMed

Mahaman YAR, Huang F, Kessete Afewerky H, Maibouge TMS, Ghose B, Wang X. Involvement of calpain in the neuropathogenesis of Alzheimer’s disease. Med Res Rev. 2019;39:608–30. PubMed PMC

Higuchi M, Iwata N, Matsuba Y, Takano J, Suemoto T, Maeda J, et al. Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology. FASEB J. 2012;26:1204–17. PubMed

Reed T, Perluigi M, Sultana R, Pierce WM, Klein JB, Turner DM, et al. Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: Insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer’s disease. Neurobiol Dis. 2008;30:107–20. PubMed

Chan HH, Leong CO, Lim CL, Koh RY. Roles of receptor-interacting protein kinase 1 in SH-SY5Y cells with beta amyloid-induced neurotoxicity. J Cell Mol Med. 2022;26:1434–44. PubMed PMC

Abdelhady R, Younis NS, Ali O, Shehata S, Sayed RH, Nadeem RI. Cognitive enhancing effects of pazopanib in D-galactose/ovariectomized Alzheimer’s rat model: insights into the role of RIPK1/RIPK3/MLKL necroptosis signaling pathway. Inflammopharmacology. 2023;31:2719–29. PubMed PMC

Sun LM, Wang HY, Wang ZG, He SD, Chen S, Liao DH, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213–27. PubMed

Han CY, Yang Y, Guan QB, Zhang XL, Shen HP, Sheng YJ, et al. New mechanism of nerve injury in Alzheimer’s disease: β-amyloid-induced neuronal pyroptosis. J Cell Mol Med. 2020;24:8078–90. PubMed PMC

Tan MA, Ishikawa H, An SSA. Exhibits in vitro anti-amyloidogenic activity and promotes neuroprotective effects in amyloid-β-induced SH-SY5Y Cells. Nutrients. 2022;14:3962. PubMed PMC

Guo YL, Fan ZY, Zhao S, Yu W, Hou XY, Nie SJ, et al. Brain-targeted lycopene-loaded microemulsion modulates neuroinflammation, oxidative stress, apoptosis and synaptic plasticity in β-amyloid-induced Alzheimer’s disease mice. Neurol Res. 2023;45:753–64. PubMed

Zhou XP, Tang XM, Li T, Li DD, Gong ZT, Zhang XJ, et al. Inhibition of VDAC1 rescues A-induced mitochondrial dysfunction and ferroptosis via activation of AMPK and Wnt/-Catenin Pathways. Mediat Inflamm. 2023;2023:6739691. PubMed PMC

Kurouski D, Lu XF, Popova L, Wan W, Shanmugasundaram M, Stubbs G, et al. Is Supramolecular filament chirality the underlying cause of major morphology differences in amyloid fibrils? J Am Chem Soc. 2014;136:2302–12. PubMed PMC

Pazderkova M, Pazderka T, Shanmugasundaram M, Dukor RK, Lednev IK, Nafie LA. Origin of enhanced VCD in amyloid fibril spectra: effect of deuteriation and pH. Chirality. 2017;29:469–75. PubMed

Wesén E, Jeffries GDM, Dzebo MM, Esbjörner EK. Endocytic uptake of monomeric amyloid-β peptides is clathrin- and dynamin-independent and results in selective accumulation of Aβ(1–42) compared to Aβ(1–40). Sci Rep-Uk. 2017;7:2021. PubMed PMC

Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, et al. β-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci. 2001;21:7551–60. PubMed PMC

Sharma VK, Singh TG, Singh S, Garg N, Dhiman S. Apoptotic pathways and Alzheimer’s disease: probing therapeutic potential. Neurochem Res. 2021;46:3103–22. PubMed

Kole AJ, Annis RP, Deshmukh M. Mature neurons: equipped for survival. Cell Death Dis. 2013;4: e689. PubMed PMC

Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J Cell Biol. 2004;165:347–56. PubMed PMC

Kam MK, Kim B, Lee DG, Lee HJ, Park YH, Lee DS. Amyloid beta oligomers-induced parkin aggravates ER stress-mediated cell death through a positive feedback loop. Neurochem Int. 2022;155: 105312. PubMed

Hu H, Tian MX, Ding C, Yu SQ. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 2019;9:3083. PubMed PMC

Zhang FL, Qi Y, Li J, Liu BY, Liu ZH, Cui XL. Activin a induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway. Oncol Rep. 2024;51:29. PubMed PMC

Esposito L, Raber J, Kekonius L, Yan FR, Yu GQ, Bien-Ly N, et al. Reduction in mitochondrial superoxide dismutase modulates Alzheimer’s disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J Neurosci. 2006;26:5167–79. PubMed PMC

Fracassi A, Marcatti M, Zolochevska O, Tabor N, Woltjer R, Moreno S, et al. Oxidative damage and antioxidant response in frontal cortex of demented and nondemented individuals with Alzheimer’s neuropathology. J Neurosci. 2021;41:538–54. PubMed PMC

Olajide OJ, La Rue C, Bergdahl A, Chapman CA. Inhibiting amyloid beta (1–42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex. Front Aging Neurosci. 2022;14: 960314. PubMed PMC

Yoon EJ, Park HJ, Kim GY, Cho HM, Choi JH, Park HY, et al. Intracellular amyloid beta interacts with SOD1 and impairs the enzymatic activity of SOD1: implications for the pathogenesis of amyotrophic lateral sclerosis. Exp Mol Med. 2009;41:611–7. PubMed PMC

Murakami K, Murata N, Noda Y, Tahara S, Kaneko T, Kinoshita N, et al. SOD1 (Copper/Zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer disease. J Biol Chem. 2011;286:44557–68. PubMed PMC

Durán-González J, Michi ED, Elorza B, Perez-Córdova MG, Pacheco-Otalora LF, Touhami A, et al. Amyloid β peptides modify the expression of antioxidant repair enzymes and a potassium channel in the septohippocampal system. Neurobiol Aging. 2013;34:2071–6. PubMed PMC

Norambuena A, Sun XH, Wallrabe H, Cao RF, Sun ND, Pardo E, et al. SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers. Neurobiol Dis. 2022;169: 105737. PubMed PMC

Porcellotti S, Fanelli F, Fracassi A, Sepe S, Cecconi F, Bernardi C, et al. Oxidative stress during the progression of β-amyloid pathology in the neocortex of the Tg2576 mouse model of Alzheimer’s disease. Oxid Med Cell Longev. 2015;2015: 967203. PubMed PMC

Ortiz JMP, Swerdlow RH. Mitochondrial dysfunction in Alzheimer’s disease: role in pathogenesis and novel therapeutic opportunities. Br J Pharmacol. 2019;176:3489–507. PubMed PMC

Schagger H, Ohm TG. Human-diseases with defects in oxidative-phosphorylation. 2. F1f0 Atp-synthase defects in Alzheimer-disease revealed by blue native polyacrylamide-gel electrophoresis. Eur J Biochem. 1995;227:916–21. PubMed

Terni B, Boada J, Portero-Otin M, Pamplona R, Ferrer I. Mitochondrial ATP-synthase in the entorhinal cortex is a target of oxidative stress at stages I/II of Alzheimer’s disease pathology. Brain Pathol. 2010;20:222–33. PubMed PMC

Kunkel GH, Chaturvedi P, Tyagi SC. Mitochondrial pathways to cardiac recovery: TFAM. Heart Fail Rev. 2016;21:499–517. PubMed PMC

Chew K, Zhao L. Interactions of mitochondrial transcription factor a with DNA damage: mechanistic insights and functional implications. Genes (Basel). 2021;12:1246. PubMed PMC

Zhao M, Wang YZ, Li L, Liu SY, Wang CS, Yuan YJ, et al. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics. 2021;11:1845–63. PubMed PMC

Ho CL, Kao NJ, Lin CI, Cross TWL, Lin SH. Quercetin increases mitochondrial biogenesis and reduces free radicals in neuronal SH-SY5Y Cells. Nutrients. 2022;14:3310. PubMed PMC

Sheng BY, Wang XL, Su B, Lee HG, Casadesus G, Perry G, et al. Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem. 2012;120:419–29. PubMed PMC

Aguirre-Rueda D, Guerra-Ojeda S, Aldasoro M, Iradi A, Obrador E, Ortega A, et al. Astrocytes protect neurons from Aβ peptide-induced neurotoxicity increasing TFAM and PGC-1 and decreasing PPAR-γ and SIRT-1. Int J Med Sci. 2015;12:48–56. PubMed PMC

Ciudad S, Puig E, Botzanowski T, Meigooni M, Arango AS, Do J, et al. Aβ(1–42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage. Nat Commun. 2020;11:3014. PubMed PMC

Song LL, Qu YQ, Tang YP, Chen X, Lo HH, Qu LQ, et al. Hyperoside alleviates toxicity of β-amyloid via endoplasmic reticulum-mitochondrial calcium signal transduction cascade in APP/PS1 double transgenic Alzheimer’s disease mice. Redox Biol. 2023;61: 102637. PubMed PMC

Wilhelmus MMM, Boelens WC, Otte-Höller I, Kamps B, de Waal RMW, Verbeek MM. Small heat shock proteins inhibit amyloid-β protein aggregation and cerebrovascular amyloid-β protein toxicity. Brain Res. 2006;1089:67–78. PubMed

Beretta G, Shala AL. Impact of heat shock proteins in neurodegeneration: possible therapeutical targets. Ann Neurosci. 2022;29:71–82. PubMed PMC

Franklin TB, Krueger-Naug AM, Clarke DB, Arrigo AP, Currie RW. The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperther. 2005;21:379–92. PubMed

Evans CG, Wisén S, Gestwicki JE. Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1–42) aggregation. J Biol Chem. 2006;281:33182–91. PubMed

Koper MJ, Van Schoor E, Ospitalieri S, Vandenberghe R, Vandenbulcke M, von Arnim CAF, et al. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease. Acta Neuropathol. 2020;139:463–84. PubMed

Salvadores N, Moreno-Gonzalez I, Gamez N, Quiroz G, Vegas-Gomez L, Escandón M, et al. Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease. Acta Neuropathol Commun. 2022;10:31. PubMed PMC

Hernández DE, Salvadores NA, Moya-Alvarado G, Catalán RJ, Bronfman FC, Court FA. Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis. J Cell Sci. 2018;131:214684. PubMed

Arrázola MS, Saquel C, Catalán RJ, Barrientos SA, Hernandez DE, Martínez NW, et al. Axonal degeneration is mediated by necroptosis activation. J Neurosci. 2019;39:3832–44. PubMed PMC

Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K. Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry US. 2002;41:7385–90. PubMed

Yanagisawa M, Ariga T, Yu RK. Cytotoxic effects of G(M1) ganglioside and amyloid beta-peptide on mouse embryonic neural stem cells. ASN Neuro. 2010;2: e00029. PubMed PMC

Nicastro MC, Spigolon D, Librizzi F, Moran O, Ortore MG, Bulone D, et al. Amyloid β-peptide insertion in liposomes containing GM1-cholesterol domains. Biophys Chem. 2016;208:9–16. PubMed

Matsubara T, Nishihara M, Yasumori H, Nakai M, Yanagisawa K, Sato T. Size and shape of amyloid fibrils induced by ganglioside nanoclusters: role of sialyl oligosaccharide in fibril formation. Langmuir. 2017;33:13874–81. PubMed

Ahyayauch H, de la Arada I, Masserini ME, Arrondo JLR, Goñi FM, Alonso A. The binding of Aβ42 peptide monomers to sphingomyelin/cholesterol/ganglioside bilayers assayed by density gradient ultracentrifugation. Int J Mol Sci. 2020;21:1674. PubMed PMC

Matsuzaki K. Abeta-ganglioside interactions in the pathogenesis of Alzheimer’s disease. Biochim Biophys Acta Biomembr. 2020;1862: 183233. PubMed

Jiang L, Bechtel MD, Bean JL, Winefield R, Williams TD, Zaidi A, et al. Effects of gangliosides on the activity of the plasma membrane Ca-ATPase. BBA Biomembranes. 2014;1838:1255–65. PubMed PMC

Amaro M, Sachl R, Aydogan G, Mikhalyov II, Vácha R, Hof M. GM ganglioside Inhibits β-amyloid oligomerization induced by sphingomyelin. Angew Chem Int Edit. 2016;55:9411–5. PubMed PMC

Owen MC, Kulig W, Poojari C, Rog T, Strodel B. Physiologically-relevant levels of sphingomyelin, but not GM1, induces a beta-sheet-rich structure in the amyloid-beta(1–42) monomer. Biochim Biophys Acta Biomembr. 2018;1860:1709–20. PubMed

Carrotta R, Mangione MR, Librizzi F, Moran O. Small Angle X-ray scattering sensing membrane composition: the role of sphingolipids in membrane-amyloid β-peptide interaction. Biology (Basel). 2022;11:26. PubMed PMC