{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T22:31:06Z","timestamp":1790029866688,"version":"4.0.1"},"reference-count":94,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cComite para el Desarrollo y la investigaci\u00f3n\u201d CODI","award":["2024-68010"],"award-info":[{"award-number":["2024-68010"]}]},{"name":"\u201cComite para el Desarrollo y la investigaci\u00f3n\u201d CODI","award":["1RF1AG062479-01"],"award-info":[{"award-number":["1RF1AG062479-01"]}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["2024-68010"],"award-info":[{"award-number":["2024-68010"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["1RF1AG062479-01"],"award-info":[{"award-number":["1RF1AG062479-01"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Familial Alzheimer\u2019s disease (FAD) caused by presenilin 1 (PSEN1) E280A induces the aberrant accumulation of intracellular A\u03b2 (iA\u03b2) in cholinergic-like neurons (ChLNs). How early iA\u03b2 accumulates in the development of ChLNs is still unknown. Consequently, the timing of appropriate therapeutic approaches against FAD is unclear. To determine the earliest iA\u03b2 in PSEN1 E280A ChLNs, flow cytometry and immunofluorescence microscopy were used to follow the development of menstrual mesenchymal stromal cells (MenSCs) into ChLNs (proliferation marker Ki67, cluster of differentiation 73 (CD73), neuronal nuclei (NeuN) marker, choline acetyl transferase (ChAT)), the kinetics of iA\u03b2 accumulation, and the simultaneous evaluation of other associated markers (e.g., DJ-1C106-SO3; lysosomes; phosphatidylethanolamine-conjugated microtubule-associated protein 1A\/1B light chain 3, LC3-II; cleaved caspase 3 (CC3)) at 0, 1, 3, 5, and 7 days. To reverse the PSEN1 E280A phenotype, we used rapamycin (RAP), verubecestat (VER), compound E (CE), epigallocatechin-3-gallate (EGCG), and tramiprosate (TM) in WT and mutant ChLNs. We found that PSEN1 E280A did not induce significant differences in the NeuN marker and ChAT in MenSCs transitioning to ChLNs. The iA\u03b2 accumulates at the earliest cholinergic developmental stage from day 0 (18%, at MenSCs stage) to day 7 (46%, at ChLNs stage), i.e., iA\u03b2 increased +156% in mutant compared to WT cells (1\u20136%). A significant increase in DJ-1C106-SO3 occurs only at day 7 (+250%). While neither CC3 (0\u20131%) nor lysosomes were different between WT and mutant cells at any time point, a stepwise increase in autophagosome accumulation was observed from day 3 (15%) to day 7 (79%), i.e., +427%, in mutant cells. While neither RAP, VER, nor CE was able to completely reduce all PSEN1 E280A-induced markers in ChLNs, the combination of EGCG and TM was more effective in removing these markers than EGCG and TM alone in PSEN1 E280A ChLNs. Given that this investigation is based on a single menstrual blood sample from WT and PSEN1 E280A, our results should be considered exploratory. Larger sample sizes are needed.<\/jats:p>","DOI":"10.3390\/ijms26083756","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T08:09:17Z","timestamp":1744790957000},"page":"3756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Combination of Epigallocatechin-3-Gallate and Tramiprosate Prevent Accumulation of Intracellular A\u03b2 and Dysfunctional Autophagy\u2013Lysosomal Pathway at Earliest Stage of Transdifferentiation of Mesenchymal Stromal Cells into PSEN1 E280A Cholinergic-like Neurons"],"prefix":"10.3390","volume":"26","author":[{"given":"Viviana","family":"Soto-Mercado","sequence":"first","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8824-379X","authenticated-orcid":false,"given":"Miguel","family":"Mendivil-Perez","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Faculty of Nursing, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-2386","authenticated-orcid":false,"given":"Marlene","family":"Jimenez-Del-Rio","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-0411","authenticated-orcid":false,"given":"Carlos","family":"Velez-Pardo","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/ibra.12181","article-title":"Global, regional, and national burdens of Alzheimer\u2019s disease and other forms of dementia in the elderly population from 1999 to 2019: A trend analysis based on the Global Burden of Disease Study 2019","volume":"10","author":"Su","year":"2024","journal-title":"Ibrain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1534","DOI":"10.1016\/S2214-109X(24)00264-X","article-title":"The global macroeconomic burden of Alzheimer\u2019s disease and other dementias: Estimates and projections for 152 countries or territories","volume":"12","author":"Chen","year":"2024","journal-title":"Lancet Glob. Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.ncl.2017.01.005","article-title":"Early-Onset Alzheimer Disease","volume":"35","author":"Mendez","year":"2017","journal-title":"Neurol. Clin."},{"key":"ref_4","first-page":"34","article-title":"Early-onset Alzheimer Disease and Its Variants","volume":"25","author":"Mendez","year":"2019","journal-title":"Continuum"},{"key":"ref_5","first-page":"43","article-title":"Molecular Genetics of Early- and Late-Onset Alzheimer\u2019s Disease","volume":"21","author":"Uddin","year":"2021","journal-title":"Curr. Gene Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s12276-022-00754-8","article-title":"\u03b3-Secretase in Alzheimer\u2019s disease","volume":"54","author":"Hur","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E476","DOI":"10.1073\/pnas.1618657114","article-title":"Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of A\u03b242 and A\u03b240 peptides by \u03b3-secretase","volume":"114","author":"Sun","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"174","DOI":"10.4103\/NRR.NRR-D-23-01781","article-title":"Emerging structures and dynamic mechanisms of \u03b3-secretase for Alzheimer\u2019s disease","volume":"20","author":"Miao","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Do, H.N., Devkota, S., Bhattarai, A., Wolfe, M.S., and Miao, Y. (2023). Effects of presenilin-1 familial Alzheimer\u2019s disease mutations on \u03b3-secretase activation for cleavage of amyloid precursor protein. Commun. Biol., 6.","DOI":"10.1038\/s42003-023-04539-1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.cell.2010.05.008","article-title":"Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations","volume":"141","author":"Lee","year":"2010","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1523\/JNEUROSCI.5156-10.2010","article-title":"Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a \u03b3-secretase-independent manner","volume":"31","author":"Neely","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.apsb.2022.01.008","article-title":"Impairment of the autophagy-lysosomal pathway in Alzheimer\u2019s diseases: Pathogenic mechanisms and therapeutic potential","volume":"12","author":"Zhang","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.celrep.2015.07.050","article-title":"Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification","volume":"12","author":"Lee","year":"2015","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9513","DOI":"10.1073\/pnas.90.20.9513","article-title":"Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides","volume":"90","author":"Wertkin","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrn2168","article-title":"Intracellular amyloid-beta in Alzheimer\u2019s disease","volume":"8","author":"LaFerla","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3233\/JAD-2004-6301","article-title":"Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex","volume":"6","author":"Echeverria","year":"2004","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/pin.12520","article-title":"Plaque formation and the intraneuronal accumulation of \u03b2-amyloid in Alzheimer\u2019s disease","volume":"67","author":"Takahashi","year":"2017","journal-title":"Pathol. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s00401-021-02345-9","article-title":"Neuronal spreading and plaque induction of intracellular A\u03b2 and its disruption of A\u03b2 homeostasis","volume":"142","author":"Roos","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"719","DOI":"10.3233\/JAD-230349","article-title":"Intracellular Amyloid-\u03b2 in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer\u2019s Disease","volume":"95","author":"Hormann","year":"2023","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gallego Villarejo, L., Bachmann, L., Marks, D., Brachth\u00e4user, M., Geidies, A., and M\u00fcller, T. (2022). Role of Intracellular Amyloid \u03b2 as Pathway Modulator, Biomarker, and Therapy Target. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094656"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"921","DOI":"10.3233\/ADR-230037","article-title":"Principles of Design of Clinical Trials for Prevention and Treatment of Alzheimer\u2019s Disease and Aging-Associated Cognitive Decline in the ACH2.0 Perspective: Potential Outcomes, Challenges, and Solutions","volume":"7","author":"Volloch","year":"2023","journal-title":"J. Alzheimer\u2019s Dis. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12154-008-0003-5","article-title":"Rapamycin and mTOR kinase inhibitors","volume":"1","author":"Ballou","year":"2008","journal-title":"J. Chem. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cmet.2014.01.001","article-title":"Rapamycin: One drug, many effects","volume":"19","author":"Li","year":"2014","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.bmcl.2018.12.049","article-title":"New evolutions in the BACE1 inhibitor field from 2014 to 2018","volume":"29","author":"Hsiao","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34086","DOI":"10.1074\/jbc.M005430200","article-title":"Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors","volume":"275","author":"Seiffert","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1080\/15548627.2023.2175569","article-title":"Rapamycin and Alzheimer disease: A hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease","volume":"19","author":"Carosi","year":"2023","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"363ra150","DOI":"10.1126\/scitranslmed.aad9704","article-title":"The BACE1 inhibitor verubecestat (MK-8931) reduces CNS \u03b2-amyloid in animal models and in Alzheimer\u2019s disease patients","volume":"8","author":"Kennedy","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.3233\/JAD-170056","article-title":"Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-A\u03b2PPswe Mice Without Inducing Microhemorrhage","volume":"59","author":"Villarreal","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/17460441.2023.2277350","article-title":"\u03b3-Secretase: Once and future drug target for Alzheimer\u2019s disease","volume":"19","author":"Wolfe","year":"2024","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/jnc.14036","article-title":"Is sporadic Alzheimer\u2019s disease a developmental disorder","volume":"143","author":"Arendt","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"90","DOI":"10.33597\/aimm.02-1007","article-title":"Alzheimer\u2019s Disease is Driven by Intraneuronally Retained Beta-Amyloid Produced in the AD-Specific, \u03b2APP-Independent Pathway: Current Perspective and Experimental Models for Tomorrow","volume":"2","author":"Volloch","year":"2020","journal-title":"Ann. Integr. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s00401-024-02799-7","article-title":"Autophagy-lysosomal-associated neuronal death in neurodegenerative disease","volume":"148","author":"Nixon","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/ng1095-219","article-title":"The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families","volume":"11","author":"Clark","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S277","DOI":"10.1016\/j.jalz.2013.09.005","article-title":"Origin of the PSEN1 E280A mutation causing early-onset Alzheimer\u2019s disease","volume":"10","author":"Lalli","year":"2014","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1001\/jama.1997.03540340027028","article-title":"Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation","volume":"277","author":"Lopera","year":"1997","journal-title":"JAMA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1093\/brain\/awaa012","article-title":"Basal forebrain volume reliably predicts the cortical spread of Alzheimer\u2019s degeneration","volume":"143","author":"Kronbichler","year":"2020","journal-title":"Brain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/ana.20100","article-title":"Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum","volume":"55","author":"Mesulam","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1001\/jamaneurol.2019.3606","article-title":"Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease","volume":"77","author":"Duara","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Mieling, M., Meier, H., and Bunzeck, N. (2023). Structural degeneration of the nucleus basalis of Meynert in mild cognitive impairment and Alzheimer\u2019s disease\u2014Evidence from an MRI-based meta-analysis. Neurosci. Biobehav. Rev., 154.","DOI":"10.1016\/j.neubiorev.2023.105393"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jneumeth.2018.11.019","article-title":"Direct transdifferentiation of human Wharton\u2019s jelly mesenchymal stromal cells into cholinergic-like neurons","volume":"312","year":"2019","journal-title":"J. Neurosci. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Soto-Mercado, V., Mendivil-Perez, M., Velez-Pardo, C., Lopera, F., and Jimenez-Del-Rio, M. (2020). Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer\u2019s disease reveal intraneuronal sAPP\u03b2 fragments accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ dysregulation: Therapeutic implications. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0221669"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","article-title":"Amyloid-\u03b2 and tau: The trigger and bullet in Alzheimer disease pathogenesis","volume":"71","author":"Bloom","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1093\/jnen\/nly059","article-title":"\u03b2-Amyloid Induces Pathology-Related Patterns of Tau Hyperphosphorylation at Synaptic Terminals","volume":"77","author":"Wu","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S359","DOI":"10.3233\/JAD-201045","article-title":"Multi-Target Effects of the Cannabinoid CP55940 on Familial Alzheimer\u2019s Disease PSEN1 E280A Cholinergic-Like Neurons: Role of CB1 Receptor","volume":"82","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"110152","DOI":"10.1016\/j.neuropharm.2024.110152","article-title":"Minocycline mitigates A\u03b2 and TAU pathology, neuronal dysfunction, and death in the PSEN1 E280A cholinergic-like neurons model of familial Alzheimer\u2019s disease","volume":"261","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"639","DOI":"10.3233\/JAD-231169","article-title":"Sildenafil Reverses the Neuropathological Alzheimer\u2019s Disease Phenotype in Cholinergic-Like Neurons Carrying the Presenilin 1 E280A Mutation","volume":"99","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Soto-Mercado, V., Mendivil-Perez, M., Velez-Pardo, C., and Jimenez-Del-Rio, M. (2021). (-)-Epigallocatechin-3-Gallate Diminishes Intra-and Extracellular Amyloid-Induced Cytotoxic Effects on Cholinergic-like Neurons from Familial Alzheimer\u2019s Disease PSEN1 E280A. Biomolecules, 11.","DOI":"10.3390\/biom11121845"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.3233\/JAD-220903","article-title":"Neuroprotective Effect of Combined Treatment with Epigallocatechin 3-Gallate and Melatonin on Familial Alzheimer\u2019s Disease PSEN1 E280A Cerebral Spheroids Derived from Menstrual Mesenchymal Stromal Cells","volume":"99","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s40263-017-0434-z","article-title":"Elucidating the A\u03b242 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer\u2019s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data","volume":"31","author":"Kocis","year":"2017","journal-title":"CNS Drugs"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s40262-017-0608-3","article-title":"Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer\u2019s Disease","volume":"57","author":"Hey","year":"2018","journal-title":"Clin. Pharmacokinet."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gomez-Sequeda, N., Jimenez-Del-Rio, M., and Velez-Pardo, C. (2024). Combination of Tramiprosate, Curcumin, and SP600125 Reduces the Neuropathological Phenotype in Familial Alzheimer Disease PSEN1 I416T Cholinergic-like Neurons. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25094925"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Mendivil-Perez, M., Velez-Pardo, C., Lopera, F., Kosik, K.S., and Jimenez-Del-Rio, M. (2023). PSEN1 E280A Cholinergic-like Neurons and Cerebral Spheroids Derived from Mesenchymal Stromal Cells and from Induced Pluripotent Stem Cells Are Neuropathologically Equivalent. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108957"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.redox.2015.01.003","article-title":"Teaching the basics of autophagy and mitophagy to redox biologists\u2013mechanisms and experimental approaches","volume":"4","author":"Zhang","year":"2015","journal-title":"Redox Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/cyto.a.22312","article-title":"Use of LysoTracker dyes: A flow cytometric study of autophagy","volume":"85","author":"Chikte","year":"2014","journal-title":"Cytometry A"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1038\/s41467-021-22111-5","article-title":"Molecular basis of V-ATPase inhibition by bafilomycin A1","volume":"12","author":"Wang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Islam, M.R., Rauf, A., Akter, S., Akter, H., Al-Imran, M.I.K., Islam, S., Nessa, M., Shompa, C.J., Shuvo, M.N.R., and Khan, I. (2025). Epigallocatechin 3-gallate-induced neuroprotection in neurodegenerative diseases: Molecular mechanisms and clinical insights. Mol. Cell Biochem., 1\u201321.","DOI":"10.1007\/s11010-025-05211-4"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e12498","DOI":"10.1002\/trc2.12498","article-title":"APOLLOE4 Phase 3 study of oral ALZ-801\/valiltramiprosate in APOE \u03b54\/\u03b54 homozygotes with early Alzheimer\u2019s disease: Trial design and baseline characteristics","volume":"10","author":"Abushakra","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Finkbeiner, S. (2020). The Autophagy Lysosomal Pathway and Neurodegeneration. Cold Spring Harb. Perspect. Biol., 12.","DOI":"10.1101\/cshperspect.a033993"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3233\/ADR-220079","article-title":"The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept","volume":"7","author":"Volloch","year":"2023","journal-title":"J. Alzheimer\u2019s Dis. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.neuron.2015.02.010","article-title":"Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer\u2019s disease","volume":"85","author":"Xia","year":"2015","journal-title":"Neuron"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"12731","DOI":"10.1073\/pnas.1713605114","article-title":"Dominant negative effect of the loss-of-function \u03b3-secretase mutants on the wild-type enzyme through heterooligomerization","volume":"114","author":"Zhou","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.mito.2013.03.008","article-title":"Mitochondrial respiratory chain Complexes I and IV are impaired by \u03b2-amyloid via direct interaction and through Complex I-dependent ROS production, respectively","volume":"13","author":"Bobba","year":"2013","journal-title":"Mitochondrion"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Meng, X., Song, Q., Liu, Z., Liu, X., Wang, Y., and Liu, J. (2024). Neurotoxic \u03b2-amyloid oligomers cause mitochondrial dysfunction-the trigger for PANoptosis in neurons. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1400544"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"May-Panloup, P., Boguenet, M., Hachem, H.E., Bouet, P.E., and Reynier, P. (2021). Embryo and Its Mitochondria. Antioxidants, 10.","DOI":"10.3390\/antiox10020139"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.2147\/CIA.S429440","article-title":"Rapamycin Responds to Alzheimer\u2019s Disease: A Potential Translational Therapy","volume":"18","author":"Hou","year":"2023","journal-title":"Clin. Interv. Aging"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"E181","DOI":"10.1073\/pnas.1014633107","article-title":"Rapamycin induces autophagic flux in neurons","volume":"107","author":"Rubinsztein","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Svensson, J.E., Bolin, M., Thor, D., Williams, P.A., Brautaset, R., Carlsson, M., S\u00f6rensson, P., Marlevi, D., Spin-Neto, R., and Probst, M. (2024). Evaluating the effect of rapamycin treatment in Alzheimer\u2019s disease and aging using in vivo imaging: The ERAP phase IIa clinical study protocol. BMC Neurol., 24.","DOI":"10.1186\/s12883-024-03596-1"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"eaar4289","DOI":"10.1126\/scitranslmed.aar4289","article-title":"Rapamycin and Alzheimer\u2019s disease: Time for a clinical trial","volume":"11","author":"Kaeberlein","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Volloch, V., and Rits-Volloch, S. (2023). Next Generation Therapeutic Strategy for Treatment and Prevention of Alzheimer\u2019s Disease and Aging-Associated Cognitive Decline: Transient, Once-in-a-Lifetime-Only Depletion of Intraneuronal A\u03b2 (iA\u03b2) by Its Targeted Degradation via Augmentation of Intra-iA\u03b2-Cleaving Activities of BACE1 and\/or BACE2. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417586"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Naidu, A., Silverglate, B., Silverglate, M., and Grossberg, G.T. (Expert. Opin. Drug Saf., 2025). Safety concerns associated with BACE1 inhibitors\u2014past, present, and future, Expert. Opin. Drug Saf., just accepted.","DOI":"10.1080\/14740338.2025.2467811"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cellsig.2015.10.006","article-title":"Beyond \u03b3-secretase activity: The multifunctional nature of presenilins in cell signalling pathways","volume":"28","author":"Duggan","year":"2016","journal-title":"Cell Signal"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"eaau6246","DOI":"10.1126\/scitranslmed.aau6246","article-title":"Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition","volume":"11","author":"Habets","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Li, S., Wang, Z., Liu, G., and Chen, M. (2024). Neurodegenerative diseases and catechins: (-)-epigallocatechin-3-gallate is a modulator of chronic neuroinflammation and oxidative stress. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1425839"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1021\/acs.jpcb.3c07232","article-title":"Molecular Insights into the Inhibition and Disaggregation Effects of EGCG on A\u03b240 and A\u03b242 Cofibrillation","volume":"128","author":"Li","year":"2024","journal-title":"J. Phys. Chem. B"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8198","DOI":"10.12659\/MSM.911175","article-title":"Epigallocatechin Gallate Is the Most Effective Catechin Against Antioxidant Stress via Hydrogen Peroxide and Radical Scavenging Activity","volume":"24","author":"He","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/jnc.15842","article-title":"The polyphenol EGCG directly targets intracellular amyloid-\u03b2 aggregates and promotes their lysosomal degradation","volume":"166","author":"Secker","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1046\/j.1471-4159.2000.0751155.x","article-title":"Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors","volume":"75","author":"Wang","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5626","DOI":"10.1074\/jbc.275.8.5626","article-title":"beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer\u2019s disease pathology","volume":"275","author":"Wang","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0306-4522(01)00460-2","article-title":"Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer\u2019s disease","volume":"110","author":"Nagele","year":"2002","journal-title":"Neuroscience"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"384","DOI":"10.2174\/1871527322666230627123426","article-title":"Role of Alpha-7-Nicotinic Acetylcholine Receptor in Alzheimer\u2019s Disease","volume":"23","author":"Singh","year":"2024","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Liu, J., and Li, L. (2019). Targeting Autophagy for the Treatment of Alzheimer\u2019s Disease: Challenges and Opportunities. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00203"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s40263-024-01103-1","article-title":"Alzheimer\u2019s Disease: Combination Therapies and Clinical Trials for Combination Therapy Development","volume":"38","author":"Cummings","year":"2024","journal-title":"CNS Drugs"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/s40263-018-0554-0","article-title":"Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain","volume":"32","author":"Hey","year":"2018","journal-title":"CNS Drugs"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"10382","DOI":"10.1080\/10408398.2022.2068500","article-title":"Chemico-biological aspects of (-) epigallocatechin-3-gallate (EGCG) to improve its stability, bioavailability and membrane permeability: Current status and future prospects","volume":"63","author":"Sahadevan","year":"2023","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1474-4422(10)70323-9","article-title":"Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer\u2019s disease: A retrospective cohort study","volume":"10","author":"Moreno","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/S1474-4422(12)70227-2","article-title":"Florbetapir PET analysis of amyloid-\u03b2 deposition in the presenilin 1 E280A autosomal dominant Alzheimer\u2019s disease kindred: A cross-sectional study","volume":"11","author":"Fleisher","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1136\/jnnp-2012-303299","article-title":"Cortical atrophy in presymptomatic Alzheimer\u2019s disease presenilin 1 mutation carriers","volume":"84","author":"Quiroz","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1001\/jamaneurol.2015.1099","article-title":"Brain Imaging and Blood Biomarker Abnormalities in Children with Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study","volume":"72","author":"Quiroz","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"5194","DOI":"10.1007\/s12035-021-02442-6","article-title":"Latent Tri-lineage Potential of Human Menstrual Blood-Derived Mesenchymal Stromal Cells Revealed by Specific In Vitro Culture Conditions","volume":"58","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.heares.2009.05.006","article-title":"Cytoplasmic Ca(2+) concentration changes evoked by cholinergic stimulation in primary astrocyte cultures prepared from the rat cochlear nucleus","volume":"255","author":"Pap","year":"2009","journal-title":"Hear. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"C1195","DOI":"10.1152\/ajpcell.00423.2008","article-title":"Acetylcholine induces Ca2+ signaling in chicken retinal pigmented epithelial cells during dedifferentiation","volume":"296","author":"Obata","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ymeth.2015.03.027","article-title":"Flow cytometric assays for the study of autophagy","volume":"82","author":"Warnes","year":"2015","journal-title":"Methods"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Yoshii, S.R., and Mizushima, N. (2017). Monitoring and Measuring Autophagy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091865"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Lazic, S.E., Clarke-Williams, C.J., and Munaf\u00f2, M.R. (2018). What exactly is \u2019N\u2019 in cell culture and animal experiments. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2005282"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3756\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:15:41Z","timestamp":1760030141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,16]]},"references-count":94,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083756"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083756","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,16]]}}}