{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:30:07Z","timestamp":1790983807200,"version":"4.1.0"},"reference-count":118,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T00:00:00Z","timestamp":1706745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"AMED","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"AMED","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"AMED","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"AMED","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"the 24th General Assembly of the Japanese Association of Medical Sciences","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"the 24th General Assembly of the Japanese Association of Medical Sciences","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"the 24th General Assembly of the Japanese Association of Medical Sciences","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"the 24th General Assembly of the Japanese Association of Medical Sciences","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"Daiko Foundation","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"Daiko Foundation","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"Daiko Foundation","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"Daiko Foundation","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"Hirose International Scholarship Foundation","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"Hirose International Scholarship Foundation","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"Hirose International Scholarship Foundation","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"Hirose International Scholarship Foundation","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"Hori Sciences and Arts Foundation","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"Hori Sciences and Arts Foundation","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"Hori Sciences and Arts Foundation","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"Hori Sciences and Arts Foundation","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"Daiwa Securities Foundation","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"Daiwa Securities Foundation","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"Daiwa Securities Foundation","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"Daiwa Securities Foundation","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]},{"name":"Hirose Foundation","award":["C19K07846"],"award-info":[{"award-number":["C19K07846"]}]},{"name":"Hirose Foundation","award":["22K07352"],"award-info":[{"award-number":["22K07352"]}]},{"name":"Hirose Foundation","award":["JP20dk0207050h0001"],"award-info":[{"award-number":["JP20dk0207050h0001"]}]},{"name":"Hirose Foundation","award":["JP20de010702"],"award-info":[{"award-number":["JP20de010702"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Presenilin, a transmembrane protein primarily known for its role in Alzheimer\u2019s disease (AD) as part of the \u03b3-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin\u2019s diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the A\u03b242-to-A\u03b240-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin\u2019s involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.<\/jats:p>","DOI":"10.3390\/ijms25031757","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T08:44:08Z","timestamp":1706777048000},"page":"1757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer\u2019s Disease and Other Neurodegenerative Diseases"],"prefix":"10.3390","volume":"25","author":[{"given":"Yang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadequl","family":"Islam","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Michikawa","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, School of Life Dentistry at Niigata, The Nippon Dental University, Niigata 951-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,1]]},"reference":[{"key":"ref_1","first-page":"a006304","article-title":"Presenilins and \u03b3-secretase: Structure, function, and role in Alzheimer Disease","volume":"2","author":"Iwatsubo","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1172\/JCI24761","article-title":"The genetic epidemiology of neurodegenerative disease","volume":"115","author":"Bertram","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1750-1326-1-4","article-title":"Pathological and physiological functions of presenilins","volume":"1","author":"Vetrivel","year":"2006","journal-title":"Mol. Neurodegener."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1073\/pnas.94.10.5090","article-title":"Evidence for phosphorylation and oligomeric assembly of presenilin 1","volume":"94","author":"Seeger","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21435","DOI":"10.1073\/pnas.1013246107","article-title":"Activation and intrinsic gamma-secretase activity of presenilin 1","volume":"107","author":"Ahn","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/nature01506","article-title":"The role of presenilin cofactors in the gamma-secretase complex","volume":"422","author":"Takasugi","year":"2003","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/nature13567","article-title":"Three-dimensional structure of human \u03b3-secretase","volume":"512","author":"Lu","year":"2014","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"37213","DOI":"10.1074\/jbc.M303941200","article-title":"Assembly of the \u03b3-Secretase Complex Involves Early Formation of an Intermediate Subcomplex of APH-1 and Nicastrin","volume":"278","author":"LaVoie","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.semcdb.2020.02.005","article-title":"Contribution of the Presenilins in the cell biology, structure and function of \u03b3-secretase","volume":"105","author":"Wouters","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1038\/emboj.2012.79","article-title":"The mechanism of \u03b3-Secretase dysfunction in familial Alzheimer disease","volume":"31","author":"Bammens","year":"2012","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa1202753","article-title":"Clinical and biomarker changes in dominantly inherited Alzheimer\u2019s disease","volume":"367","author":"Bateman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_13","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 Abeta42 and Abeta40 peptides by gamma-secretase","volume":"114","author":"Sun","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12731","DOI":"10.1073\/pnas.1713605114","article-title":"Dominant negative effect of the loss-of-function gamma-secretase mutants on the wild-type enzyme through heterooligomerization","volume":"114","author":"Zhou","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3233\/JAD-2011-101065","article-title":"The many substrates of presenilin\/\u03b3-secretase","volume":"25","author":"Haapasalo","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31153","DOI":"10.1074\/jbc.C111.235267","article-title":"Mutations in nicastrin protein differentially affect amyloid beta-peptide production and Notch protein processing","volume":"286","author":"Wanngren","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaaw0930","DOI":"10.1126\/science.aaw0930","article-title":"Recognition of the amyloid precursor protein by human \u03b3-secretase","volume":"363","author":"Zhou","year":"2019","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.jalz.2011.02.010","article-title":"Presenilin enhancer-2 gene: Identification of a novel promoter mutation in a patient with early-onset familial Alzheimer\u2019s disease","volume":"7","author":"Andreoli","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1007\/s00415-005-0799-7","article-title":"PEN-2 gene mutation in a familial Alzheimer\u2019s disease case","volume":"252","author":"Piscopo","year":"2005","journal-title":"J. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41392-022-00934-y","article-title":"Notch signaling pathway: Architecture, disease, and therapeutics","volume":"7","author":"Zhou","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0070-2153(10)92006-1","article-title":"Gamma-secretase and the intramembrane proteolysis of Notch","volume":"92","author":"Jorissen","year":"2010","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","article-title":"The canonical Notch signaling pathway: Unfolding the activation mechanism","volume":"137","author":"Kopan","year":"2009","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/19077","article-title":"Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity","volume":"398","author":"Wolfe","year":"1999","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrm2101","article-title":"Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer\u2019s amyloid beta-peptide","volume":"8","author":"Haass","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1038\/emboj.2010.211","article-title":"Neurotoxicity of Alzheimer\u2019s disease A\u03b2 peptides is induced by small changes in the A\u03b242 to A\u03b240 ratio","volume":"29","author":"Kuperstein","year":"2010","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6318","DOI":"10.1074\/jbc.M110371200","article-title":"Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4","volume":"277","author":"Lee","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"44754","DOI":"10.1074\/jbc.M206872200","article-title":"Presenilin-dependent Intramembrane Proteolysis of CD44 Leads to the Liberation of Its Intracellular Domain and the Secretion of an A\u03b2-like Peptide","volume":"277","author":"Lammich","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/jnr.10753","article-title":"Presenilin 1 is involved in maturation and trafficking of N-cadherin to the plasma membrane","volume":"74","author":"Uemura","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1159\/000080984","article-title":"Presenilin 1 and cadherins: Stabilization of cell-cell adhesion and proteolysis-dependent regulation of transcription","volume":"1","author":"Parisiadou","year":"2004","journal-title":"Neurodegener. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.semcdb.2020.05.019","article-title":"The substrate repertoire of \u03b3-secretase\/presenilin","volume":"105","author":"Lichtenthaler","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.semcdb.2020.03.006","article-title":"Substrate recruitment by \u03b3-secretase","volume":"105","author":"Fukumori","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.semcdb.2020.04.008","article-title":"The dynamics of \u03b3-secretase and its substrates","volume":"105","author":"Hitzenberger","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nature08177","article-title":"Presenilins are essential for regulating neurotransmitter release","volume":"460","author":"Zhang","year":"2009","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.neuron.2008.04.015","article-title":"Mechanism of Ca2+ disruption in Alzheimer\u2019s disease by presenilin regulation of InsP3 receptor channel gating","volume":"58","author":"Cheung","year":"2008","journal-title":"Neuron"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0896-6273(04)00182-5","article-title":"Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration","volume":"42","author":"Saura","year":"2004","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/ni.3102","article-title":"Innate immunity in Alzheimer\u2019s disease","volume":"16","author":"Heneka","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1385\/NMM:2:1:29","article-title":"Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain","volume":"2","author":"Lee","year":"2002","journal-title":"Neuromol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.neuron.2007.07.025","article-title":"Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer\u2019s disease","volume":"55","author":"Palop","year":"2007","journal-title":"Neuron"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wirths, O., and Zampar, S. (2020). Neuron Loss in Alzheimer\u2019s Disease: Translation in Transgenic Mouse Models. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218144"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4439","DOI":"10.1523\/JNEUROSCI.18-12-04439.1998","article-title":"Increased Sensitivity to Mitochondrial Toxin-Induced Apoptosis in Neural Cells Expressing Mutant Presenilin-1 Is Linked to Perturbed Calcium Homeostasis and Enhanced Oxyradical Production","volume":"18","author":"Keller","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1111\/j.1471-4159.2005.03647.x","article-title":"Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid \u03b2-peptide (1\u201342), H2O2 and kainic acid: Implications for Alzheimer\u2019s disease","volume":"96","author":"Sultana","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/ca.23792","article-title":"Apoptosis and its therapeutic implications in neurodegenerative diseases","volume":"35","author":"Erekat","year":"2022","journal-title":"Clin. Anat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.brainres.2017.01.034","article-title":"Mutant presenilin2 promotes apoptosis through the p53\/miR-34a axis in neuronal cells","volume":"1662","author":"Li","year":"2017","journal-title":"Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1111\/j.1471-4159.2004.02895.x","article-title":"\u03b2-Site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways","volume":"92","author":"Tamagno","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1002\/jnr.22271","article-title":"Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells","volume":"88","author":"Oda","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"902525","DOI":"10.3389\/fnagi.2022.902525","article-title":"Presenilin Deficiency Increases Susceptibility to Oxidative Damage in Fibroblasts","volume":"14","author":"Zou","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12987-020-00235-y","article-title":"Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro","volume":"18","author":"Raut","year":"2021","journal-title":"Fluids Barriers CNS"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1084\/jem.20171406","article-title":"Alzheimer\u2019s disease: A matter of blood\u2013brain barrier dysfunction?","volume":"214","author":"Montagne","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Brandl, S., and Reindl, M. (2023). Blood\u2013Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612699"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.ceca.2011.05.013","article-title":"Presenilins function in ER calcium leak and Alzheimer\u2019s disease pathogenesis","volume":"50","author":"Supnet","year":"2011","journal-title":"Cell Calcium"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5180","DOI":"10.1523\/JNEUROSCI.0739-06.2006","article-title":"Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer\u2019s disease mice","volume":"26","author":"Stutzmann","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1073\/pnas.1100735108","article-title":"Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk","volume":"108","author":"Zampese","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/cdd.2010.191","article-title":"The Beclin 1 network regulates autophagy and apoptosis","volume":"18","author":"Kang","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1523\/JNEUROSCI.2610-10.2011","article-title":"Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation","volume":"31","author":"Shipton","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"T185","DOI":"10.1016\/j.jalz.2008.05.504","article-title":"O4-01\u201305: Presenilin 1 mutation promotes Tau phosphorylation and aggregation in a novel Alzheimer\u2019s disease mouse model","volume":"4","author":"Boutajangout","year":"2008","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s11064-011-0575-2","article-title":"Increased Phosphorylation of Tau and Synaptic Protein Loss in the Aged Transgenic Mice Expressing Familiar Alzheimer\u2019s Disease-Linked Presenilin 1 Mutation","volume":"37","author":"Yang","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1016\/j.neurobiolaging.2008.01.005","article-title":"Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia","volume":"30","author":"Bernardi","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s40478-021-01259-7","article-title":"Loss of presenilin function enhances tau phosphorylation and aggregation in mice","volume":"9","author":"Saura","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1021\/bi7014508","article-title":"Novel Role of Presenilins in Maturation and Transport of Integrin \u03b21","volume":"47","author":"Zou","year":"2008","journal-title":"Biochemistry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1567205043480528","article-title":"Protein trafficking and Alzheimer\u2019s disease","volume":"1","author":"Uemura","year":"2004","journal-title":"Curr. Alzheimer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.neurobiolaging.2016.10.005","article-title":"Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2","volume":"49","author":"Wang","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/S0896-6273(00)80637-6","article-title":"Effects of PS1 deficiency on membrane protein trafficking in neurons","volume":"21","author":"Naruse","year":"1998","journal-title":"Neuron"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1083\/jcb.200406060","article-title":"Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway","volume":"166","author":"Esselens","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"31504","DOI":"10.1074\/jbc.M704273200","article-title":"Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway","volume":"282","author":"Repetto","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e405","DOI":"10.1038\/emm.2017.200","article-title":"Intracellular trafficking of TREM2 is regulated by presenilin 1","volume":"49","author":"Zhao","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1523\/JNEUROSCI.2039-21.2021","article-title":"Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer\u2019s Disease Pathogenesis","volume":"42","author":"Islam","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1111\/jnc.15750","article-title":"Apolipoprotein E4 inhibits \u03b3-secretase activity via binding to the \u03b3-secretase complex","volume":"164","author":"Sun","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"8628","DOI":"10.1523\/JNEUROSCI.1549-07.2007","article-title":"Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition","volume":"27","author":"Zou","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"9760","DOI":"10.1074\/jbc.RA118.006420","article-title":"A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer\u2019s disease pathology in mice","volume":"294","author":"Liu","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1016\/j.ajpath.2013.01.053","article-title":"A\u03b243 is the earliest-depositing A\u03b2 species in APP transgenic mouse brain and is converted to A\u03b241 by two active domains of ACE","volume":"182","author":"Zou","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1098034","DOI":"10.3389\/fnagi.2023.1098034","article-title":"Presenilin 1 deficiency impairs A\u03b242-to-A\u03b240- and angiotensin-converting activities of ACE","volume":"15","author":"Gao","year":"2023","journal-title":"Front. Aging Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Colucci-D\u2019Amato, L., Speranza, L., and Volpicelli, F. (2020). Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207777"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.celrep.2019.06.054","article-title":"Deficiency in BDNF\/TrkB Neurotrophic Activity Stimulates \u03b4-Secretase by Upregulating C\/EBP\u03b2 in Alzheimer\u2019s Disease","volume":"28","author":"Wang","year":"2019","journal-title":"Cell Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40035-022-00279-0","article-title":"Brain-derived neurotrophic factor in Alzheimer\u2019s disease and its pharmaceutical potential","volume":"11","author":"Gao","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.neurobiolaging.2012.02.024","article-title":"Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors","volume":"34","author":"Barthet","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1111\/j.1460-9568.2005.04290.x","article-title":"Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3 Kinase signalling mechanism","volume":"22","author":"Elliott","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/s41419-018-0945-7","article-title":"Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing \u03b3-secretase-independent ERK\/CREB signaling","volume":"9","author":"Chong","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"13505","DOI":"10.1523\/JNEUROSCI.0918-13.2013","article-title":"Low-level laser therapy rescues dendrite atrophy via upregulating BDNF expression: Implications for Alzheimer\u2019s disease","volume":"33","author":"Meng","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.arr.2008.11.003","article-title":"Wnt signaling in Alzheimer\u2019s disease: Up or down, that is the question","volume":"8","author":"Boonen","year":"2009","journal-title":"Ageing Res. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"134345","DOI":"10.1016\/j.neulet.2019.134345","article-title":"Both Wnt\/\u03b2-catenin and ERK5 signaling pathways are involved in BDNF-induced differentiation of pluripotent stem cells into neural stem cells","volume":"708","author":"Zhang","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_81","first-page":"488","article-title":"[Expressions of synaptophysin and BDNF\/Trk-B in cerebellum of APPswe\/PS1dE9 transgenic mice]","volume":"33","author":"Dong","year":"2017","journal-title":"Zhongguo Ying Yong Sheng Li Xue Za Zhi"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"fcaa100","DOI":"10.1093\/braincomms\/fcaa100","article-title":"Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor","volume":"2","author":"Yoon","year":"2020","journal-title":"Brain Commun."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Nicoletti, V.G., Pajer, K., Calcagno, D., Pajenda, G., and N\u00f3gr\u00e1di, A. (2022). The Role of Metals in the Neuroregenerative Action of BDNF, GDNF, NGF and Other Neurotrophic Factors. Biomolecules, 12.","DOI":"10.3390\/biom12081015"},{"key":"ref_84","unstructured":"Jeon, K.W. (2015). International Review of Cell and Molecular Biology, Academic Press."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1111\/j.1471-4159.2007.04571.x","article-title":"Presenilin dependence of phospholipase C and protein kinase C signaling","volume":"102","author":"Dehvari","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Barab\u00e1s, K., Kobol\u00e1k, J., God\u00f3, S., Kov\u00e1cs, T., Ernszt, D., Kecsk\u00e9s, M., Varga, C., J\u00e1nosi, T.Z., Fujiwara, T., and Kusumi, A. (2021). Live-Cell Imaging of Single Neurotrophin Receptor Molecules on Human Neurons in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413260"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S0140-6736(04)17103-1","article-title":"Alpha-synuclein locus duplication as a cause of familial Parkinson\u2019s disease","volume":"364","author":"Kachergus","year":"2004","journal-title":"Lancet"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1111\/j.1471-4159.2008.05715.x","article-title":"Notch: From neural development to neurological disorders","volume":"107","author":"Lathia","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"428010","DOI":"10.1155\/2012\/428010","article-title":"Mechanism of oxidative stress in neurodegeneration","volume":"2012","author":"Gandhi","year":"2012","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"8417","DOI":"10.3390\/ijms24098417","article-title":"Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer&rsquo;s Disease","volume":"24","author":"Yang","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.parkreldis.2020.06.005","article-title":"A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism","volume":"77","author":"Gatto","year":"2020","journal-title":"Park. Relat. Disord."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1080\/15548627.2017.1363950","article-title":"Presenilins at the crossroad of a functional interplay between PARK2\/PARKIN and PINK1 to control mitophagy: Implication for neurodegenerative diseases","volume":"13","author":"Checler","year":"2017","journal-title":"Autophagy"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1093\/brain\/awu119","article-title":"Convergence of pathology in dementia with Lewy bodies and Alzheimer\u2019s disease: A role for the novel interaction of alpha-synuclein and presenilin 1 in disease","volume":"137","author":"Winslow","year":"2014","journal-title":"Brain"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"208.e11","DOI":"10.1016\/j.neurobiolaging.2015.09.016","article-title":"Pilot whole-exome sequencing of a German early-onset Alzheimer\u2019s disease cohort reveals a substantial frequency of PSEN2 variants","volume":"37","author":"Blauwendraat","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1177\/1533317506290448","article-title":"Frontotemporal dementia-like phenotypes associated with presenilin-1 mutations","volume":"21","author":"Mendez","year":"2006","journal-title":"Am. J. Alzheimer\u2019s Dis. Other Dement."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1002\/ana.20103","article-title":"Presenilin mutations associated with fronto-temporal dementia","volume":"55","author":"Hutton","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1097\/00001756-200205070-00036","article-title":"Alternative transcripts of presenilin-1 associated with frontotemporal dementia","volume":"13","author":"Evin","year":"2002","journal-title":"Neuroreport"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1042\/BST0330559","article-title":"Presenilin 1: More than just \u03b3-secretase","volume":"33","author":"Raemaekers","year":"2005","journal-title":"Biochem. Soc. Trans."},{"key":"ref_99","first-page":"240","article-title":"Electron microscope and enzyme studies in cerebral biopsies of Huntington\u2019s chorea","volume":"99","author":"Roizin","year":"1974","journal-title":"Trans. Am. Neurol. Assoc."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7268","DOI":"10.1523\/JNEUROSCI.20-19-07268.2000","article-title":"Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy","volume":"20","author":"Kegel","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1016\/j.biocel.2004.05.008","article-title":"Involvement of macroautophagy in the dissolution of neuronal inclusions","volume":"36","author":"Rideout","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_102","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_103","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_104","doi-asserted-by":"crossref","first-page":"721047","DOI":"10.3389\/fnmol.2021.721047","article-title":"Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome","volume":"14","author":"Jaijo","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1111\/bph.12476","article-title":"Mitochondrial dysfunction in amyotrophic lateral sclerosis\u2014A valid pharmacological target?","volume":"171","author":"Muyderman","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Zhao, J., Wang, X., Huo, Z., Chen, Y., Liu, J., Zhao, Z., Meng, F., Su, Q., Bao, W., and Zhang, L. (2022). The Impact of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis. Cells, 11.","DOI":"10.3390\/cells11132049"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e33052","DOI":"10.7554\/eLife.33052","article-title":"Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans","volume":"7","author":"Sarasija","year":"2018","journal-title":"eLife"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"7284967","DOI":"10.1155\/2019\/7284967","article-title":"Presenilin 1 Regulates [Ca2+]i and Mitochondria\/ER Interaction in Cultured Rat Hippocampal Neurons","volume":"2019","author":"Korkotian","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1126\/science.1154584","article-title":"TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis","volume":"319","author":"Sreedharan","year":"2008","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"8083","DOI":"10.1074\/jbc.M808064200","article-title":"Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1","volume":"284","author":"Kim","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Couthouis, J., RAPHael, A.R., Daneshjou, R., and Gitler, A.D. (2014). Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004704"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.bbrc.2019.05.185","article-title":"Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer\u2019s pedigrees and their functional characterization","volume":"516","author":"Shen","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.trci.2018.11.004","article-title":"FDA position statement \u201cEarly Alzheimer\u2019s disease: Developing drugs for treatment, Guidance for Industry\u201d","volume":"5","author":"Sabbagh","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1212\/01.wnl.0000260698.46517.8f","article-title":"Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment","volume":"68","author":"Scheff","year":"2007","journal-title":"Neurology"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s40120-020-00218-z","article-title":"CRISPR-Cas9: A Promising Genome Editing Therapeutic Tool for Alzheimer\u2019s Disease-A Narrative Review","volume":"9","author":"Barman","year":"2020","journal-title":"Neurol. Ther."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.omtn.2022.03.022","article-title":"CRISPR-Cas9 treatment partially restores amyloid-\u03b2 42\/40 in human fibroblasts with the Alzheimer\u2019s disease PSEN 1 M146L mutation","volume":"28","author":"Konstantinidis","year":"2022","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_117","first-page":"1679","article-title":"Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: Lessons from recent clinical trials","volume":"18","author":"Imbimbo","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1056\/NEJMoa1210951","article-title":"A phase 3 trial of semagacestat for treatment of Alzheimer\u2019s disease","volume":"369","author":"Doody","year":"2013","journal-title":"N. Engl. J. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1757\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:52:54Z","timestamp":1760104374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,1]]},"references-count":118,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25031757"],"URL":"https:\/\/doi.org\/10.3390\/ijms25031757","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,1]]}}}