{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:28:59Z","timestamp":1790742539025,"version":"4.1.0"},"reference-count":94,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T00:00:00Z","timestamp":1729555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft"},{"name":"University of Bielefeld"},{"name":"FBMB e.V."},{"name":"Hans B\u00f6ckler Stiftung"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a devasting neurodegenerative disease afflicting mainly glutamatergic neurons together with a massive neuroinflammation mediated by the transcription factor NF-\u03baB. A 65%-plus increase in Alzheimer\u2019s patients by 2050 might be a major threat to society. Hallmarks of AD are neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and amyloid beta (A\u03b2) plaques. Here, we review the potential involvement of transcription factor NF-\u03baB by hereditary mutations of the tumor necrosis factor pathway in AD patients. One of the greatest genetic risk factors is APOE4. Recently, it was shown that the APOE4 allele functions as a null allele in human astrocytes not repressing NF-\u03baB anymore. Moreover, NF-\u03baB seems to be involved in the repair of DNA double-strand breaks during healthy learning and memory, a function blunted in AD. NF-\u03baB could be a friend to healthy neurons by repressing apoptosis and necroptosis. But a loss of neuronal NF-\u03baB and activation of glial NF-\u03baB in AD makes it a foe of neuronal survival. Hopeful therapies include TNFR2 receptor bodies relieving the activation of glial NF-\u03baB by TNF\u03b1.<\/jats:p>","DOI":"10.3390\/ijms252111353","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T06:11:25Z","timestamp":1729577485000},"page":"11353","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["NF-\u03baB in Alzheimer\u2019s Disease: Friend or Foe? Opposite Functions in Neurons and Glial Cells"],"prefix":"10.3390","volume":"25","author":[{"given":"Barbara","family":"Kaltschmidt","sequence":"first","affiliation":[{"name":"Molecular Neurobiology, University of Bielefeld, 33615 Bielefeld, Germany"},{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, Ostwestfalen-Lippe (OWL) (FBMB E.V.), 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nele Johanne","family":"Czaniera","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Schulten","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kaltschmidt","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, Ostwestfalen-Lippe (OWL) (FBMB E.V.), 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/BF02866241","article-title":"\u00fcber eigenartige Krankheitsf\u00e4lle des sp\u00e4teren Alters","volume":"4","author":"Alzheimer","year":"1911","journal-title":"Z F\u00fcr Gesamte Neurol. Psychiatr."},{"key":"ref_2","first-page":"a006189","article-title":"Neuropathological Alterations in Alzheimer Disease","volume":"1","author":"Frosch","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/alz.12192","article-title":"Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer\u2019s disease","volume":"17","author":"Arnsten","year":"2021","journal-title":"Alzheimers Dement. J. Alzheimers Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of A\u03b2-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13024-024-00722-y","article-title":"The endotoxin hypothesis of Alzheimer\u2019s disease","volume":"19","author":"Brown","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1212\/WNL.0000000000003391","article-title":"Gram-negative bacterial molecules associate with Alzheimer disease pathology","volume":"87","author":"Zhan","year":"2016","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/ana.20009","article-title":"Imaging brain amyloid in Alzheimer\u2019s disease with Pittsburgh Compound-B","volume":"55","author":"Klunk","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1001\/jama.2024.13855","article-title":"Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care","volume":"332","author":"Palmqvist","year":"2024","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The neuropathological diagnosis of Alzheimer\u2019s disease","volume":"14","author":"DeTure","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.neurobiolaging.2007.10.015","article-title":"White matter loss in healthy ageing: A postmortem analysis","volume":"30","author":"Piguet","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1212\/WNL.0b013e3182166e96","article-title":"Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults","volume":"76","author":"Dickerson","year":"2011","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-12679-1_1","article-title":"Neuroanatomy and pathology of sporadic Alzheimer\u2019s disease","volume":"215","author":"Braak","year":"2015","journal-title":"Advances in Anatomy, Embryology and Cell Biology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00401-014-1375-y","article-title":"Neuropathology and biochemistry of A\u03b2 and its aggregates in Alzheimer\u2019s disease","volume":"129","author":"Thal","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/s41593-022-01084-8","article-title":"Faulty autolysosome acidification in Alzheimer\u2019s disease mouse models induces autophagic build-up of A\u03b2 in neurons, yielding senile plaques","volume":"25","author":"Lee","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0006-8993(96)01073-6","article-title":"Enhancement of immunoreactivity for NF-kappa B in human cerebral infarctions","volume":"739","author":"Terai","year":"1996","journal-title":"Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1073\/pnas.94.6.2642","article-title":"Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease","volume":"94","author":"Kaltschmidt","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1097\/00001756-199709080-00009","article-title":"Nuclear translocation of NF-\u03baB in cholinergic neurons of patients with Alzheimer\u2019s disease","volume":"8","author":"Hunot","year":"1997","journal-title":"NeuroReport"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9409","DOI":"10.1073\/pnas.96.16.9409","article-title":"Inhibition of NF-\u03baB potentiates amyloid \u03b2-mediated neuronal apoptosis","volume":"96","author":"Kaltschmidt","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1097\/00001756-200108280-00011","article-title":"Enhanced expression of I-kappaB with neurofibrillary pathology in Alzheimer\u2019s disease","volume":"12","author":"Yoshiyama","year":"2001","journal-title":"NeuroReport"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Jong Huat, T., Camats-Perna, J., Newcombe, E.A., Onraet, T., Campbell, D., Sucic, J.T., Martini, A., Forner, S., Mirzaei, M., and Poon, W. (2024). The impact of astrocytic NF-\u03baB on healthy and Alzheimer\u2019s disease brains. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-65248-1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1073\/pnas.82.12.4245","article-title":"Amyloid plaque core protein in Alzheimer disease and Down syndrome","volume":"82","author":"Masters","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/325733a0","article-title":"The precursor of Alzheimer\u2019s disease amyloid A4 protein resembles a cell-surface receptor","volume":"325","author":"Kang","year":"1987","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1086\/302553","article-title":"Early-onset autosomal dominant Alzheimer disease: Prevalence, genetic heterogeneity, and mutation spectrum","volume":"65","author":"Campion","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrn3983","article-title":"A genetic cause of Alzheimer disease: Mechanistic insights from Down syndrome","volume":"16","author":"Wiseman","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kaltschmidt, B., Helweg, L.P., Greiner, J.F.W., and Kaltschmidt, C. (2022). NF-\u03baB in neurodegenerative diseases: Recent evidence from human genetics. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.954541"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3629","DOI":"10.1002\/alz.13805","article-title":"The ABC\u2019s of Alzheimer risk gene ABCA7","volume":"20","author":"Duchateau","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"23790","DOI":"10.1073\/pnas.1908529116","article-title":"ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain","volume":"116","author":"Aikawa","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e568","DOI":"10.1212\/WNL.0000000000201489","article-title":"Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease","volume":"100","author":"Huang","year":"2023","journal-title":"Neurology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.arcmed.2014.12.006","article-title":"TNF-alpha G308A Polymorphism and the Susceptibility to Alzheimer\u2019s Disease: An Updated Meta-analysis","volume":"46","author":"Wang","year":"2015","journal-title":"Arch. Med. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.neurobiolaging.2006.02.012","article-title":"Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease","volume":"28","author":"Alvarez","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_35","first-page":"25","article-title":"TNF-alpha modulation for treatment of Alzheimer\u2019s disease: A 6-month pilot study","volume":"8","author":"Tobinick","year":"2006","journal-title":"MedGenMed Medscape Gen. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.3233\/JAD-2010-100921","article-title":"Higher serum sTNFR1 level predicts conversion from mild cognitive impairment to Alzheimer\u2019s disease","volume":"22","author":"Diniz","year":"2010","journal-title":"J. Alzheimers Dis. JAD"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"111200","DOI":"10.1016\/j.celrep.2022.111200","article-title":"APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-\u03baB activation","volume":"40","author":"Arnaud","year":"2022","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0378-1119(98)00340-0","article-title":"Functional identification of the promoter of the gene encoding the Rhesus monkey \u03b2-amyloid precursor protein","volume":"217","author":"Song","year":"1998","journal-title":"Gene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","article-title":"Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here?","volume":"17","author":"Leng","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41583-023-00776-9","article-title":"Cell type-specific roles of APOE4 in Alzheimer disease","volume":"25","author":"Blumenfeld","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0092-8674(03)00521-X","article-title":"Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes","volume":"114","author":"Micheau","year":"2003","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9348651","DOI":"10.1155\/2016\/9348651","article-title":"RAGE Expression and ROS Generation in Neurons: Differentiation versus Damage","volume":"2016","author":"Piras","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1046\/j.1471-4159.1998.70051876.x","article-title":"The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA\/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons","volume":"70","author":"Furukawa","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9077","DOI":"10.1073\/pnas.92.20.9077","article-title":"Synaptic activation of NF-kappa B by glutamate in cerebellar granule neurons in vitro","volume":"92","author":"Guerrini","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9618","DOI":"10.1073\/pnas.92.21.9618","article-title":"Stimulation of ionotropic glutamate receptors activates transcription factor NF-kappa B in primary neurons","volume":"92","author":"Kaltschmidt","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/nn1110","article-title":"NF-kappa B functions in synaptic signaling and behavior","volume":"6","author":"Meffert","year":"2003","journal-title":"Nat. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/373303a0","article-title":"Structure of NF-kappa B p50 homodimer bound to a kappa B site","volume":"373","author":"Ghosh","year":"1995","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Kaltschmidt, B., Greiner, J.F.W., Kadhim, H.M., and Kaltschmidt, C. (2018). Subunit-Specific Role of NF-\u03baB in Cancer. Biomedicines, 6.","DOI":"10.3390\/biomedicines6020044"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1038\/s41590-023-01561-7","article-title":"NF-\u03baB subunits direct kinetically distinct transcriptional cascades in antigen receptor-activated B cells","volume":"24","author":"Zhao","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s00418-014-1195-0","article-title":"Quantitative single-molecule localization microscopy combined with rule-based modeling reveals ligand-induced TNF-R1 reorganization toward higher-order oligomers","volume":"142","author":"Fricke","year":"2014","journal-title":"Histochem. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.molcel.2009.10.013","article-title":"Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction","volume":"36","author":"Haas","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1093\/jb\/mvad045","article-title":"LUBAC-mediated linear ubiquitination in tissue homeostasis and disease","volume":"174","author":"Sasaki","year":"2023","journal-title":"J. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/s41590-024-01817-w","article-title":"Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency","volume":"25","author":"Oda","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.1038\/emboj.2012.241","article-title":"Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-\u03baB regulation","volume":"31","author":"Tokunaga","year":"2012","journal-title":"EMBO J."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zhou, J., Wu, R., High, A.A., Slaughter, C.A., Finkelstein, D., Rehg, J.E., Redecke, V., and H\u00e4cker, H. (2011). A20-binding inhibitor of NF-\u03baB (ABIN1) controls Toll-like receptor-mediated CCAAT\/enhancer-binding protein \u03b2 activation and protects from inflammatory disease. Proc. Natl. Acad. Sci. USA, 108.","DOI":"10.1073\/pnas.1106232108"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wajant, H., and Siegmund, D. (2019). TNFR1 and TNFR2 in the Control of the Life and Death Balance of Macrophages. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00091"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.4103\/1673-5374.390979","article-title":"Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer\u2019s disease","volume":"19","author":"Asimakidou","year":"2024","journal-title":"Neural Regen. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s40478-021-01264-w","article-title":"TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer\u2019s disease hippocampus","volume":"9","author":"Jayaraman","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cell.2016.12.012","article-title":"30 years of NF-\u03baB: A blossoming of relevance to human pathobiology","volume":"168","author":"Zhang","year":"2017","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kaltschmidt, B., Witte, K.E., Greiner, J.F.W., Weissinger, F., and Kaltschmidt, C. (2022). Targeting NF-\u03baB Signaling in Cancer Stem Cells: A Narrative Review. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020261"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"148157","DOI":"10.1016\/j.brainres.2022.148157","article-title":"The effects of synthetic glucocorticoid treatment for inflammatory disease on brain structure, function, and dementia outcomes: A systematic review","volume":"1798","author":"Shorey","year":"2023","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3233\/JAD-190444","article-title":"Glucocorticoid Therapy is Associated with a Lower Risk of Dementia","volume":"73","author":"Nerius","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9902","DOI":"10.1073\/pnas.170173897","article-title":"Inhibition of the ubiquitin-proteasome system in Alzheimer\u2019s disease","volume":"97","author":"Lam","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1002\/alz.13680","article-title":"Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons","volume":"20","author":"Hsieh","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"403","DOI":"10.2174\/1567205014666170117141330","article-title":"Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer\u2019s Disease: Results from a Double-Blind, Placebo-Controlled Trial","volume":"14","author":"Decourt","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Jordan, F. (2020). Aspirin and Other Non-Steroidal Anti-Inflammatory Drugs for the Prevention of Dementia, Cochrane Library.","DOI":"10.1002\/14651858.CD011459.pub2"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Sivamaruthi, B.S., Raghani, N., Chorawala, M., Bhattacharya, S., Prajapati, B.G., Elossaily, G.M., and Chaiyasut, C. (2023). NF-\u03baB Pathway and Its Inhibitors: A Promising Frontier in the Management of Alzheimer\u2019s Disease. Biomedicines, 11.","DOI":"10.3390\/biomedicines11092587"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e525","DOI":"10.1038\/cddis.2013.54","article-title":"Minocycline selectively inhibits M1 polarization of microglia","volume":"4","author":"Kobayashi","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Howard, R., Zubko, O., Gray, R., Bradley, R., Harper, E., Kelly, L., Pank, L., O\u2019Brien, J., Fox, C., and Tabet, N. (2020). Minocycline 200\u2009Mg or 400\u2009Mg Versus Placebo for Mild Alzheimer\u2019s Disease: The MADE Phase II, Three-Arm RCT. Efficacy and Mechanism Evaluation, NIHR Journals Library.","DOI":"10.3310\/eme07020"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"619","DOI":"10.3233\/JAD-200711","article-title":"Therapeutic Potential of TNF- \u03b1 Inhibition for Alzheimer\u2019s Disease Prevention","volume":"78","author":"Isaacson","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.1128\/MCB.26.8.2936-2946.2006","article-title":"NF-\u03baB Regulates Spatial Memory Formation and Synaptic Plasticity through Protein Kinase A\/CREB Signaling","volume":"26","author":"Kaltschmidt","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7283","DOI":"10.1128\/MCB.00510-06","article-title":"NF-\u03baB\/Rel Regulates Inhibitory and Excitatory Neuronal Function and Synaptic Plasticity","volume":"26","author":"Raber","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5688","DOI":"10.1523\/JNEUROSCI.0111-12.2012","article-title":"I\u03baB Kinase\/Nuclear Factor \u03baB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling","volume":"32","author":"Schmeisser","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/1750-1326-8-40","article-title":"Sustained, neuron-specific IKK\/NF-\u03baB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging","volume":"8","author":"Maqbool","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e22778","DOI":"10.1096\/fj.202201512R","article-title":"Deficiency of IKK\u03b2 in neurons ameliorates Alzheimer\u2019s disease pathology in APP- and tau-transgenic mice","volume":"37","author":"Quan","year":"2023","journal-title":"FASEB J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0896-6273(03)00627-5","article-title":"Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles","volume":"40","author":"Cruz","year":"2003","journal-title":"Neuron"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"eabo4662","DOI":"10.1126\/sciadv.abo4662","article-title":"Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration","volume":"8","author":"Welch","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1073\/pnas.1222878110","article-title":"Genomic responses in mouse models poorly mimic human inflammatory diseases","volume":"110","author":"Seok","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/cyto.a.20426","article-title":"Cytometry of ATM activation and histone H2AX phosphorylation to estimate extent of DNA damage induced by exogenous agents","volume":"71","author":"Tanaka","year":"2007","journal-title":"Cytom. Part J. Int. Soc. Anal. Cytol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"12871","DOI":"10.1073\/pnas.2135498100","article-title":"Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer","volume":"100","author":"Vilenchik","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.canlet.2005.07.016","article-title":"Does gammaH2AX foci formation depend on the presence of DNA double strand breaks?","volume":"229","author":"Takahashi","year":"2005","journal-title":"Cancer Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation","volume":"421","author":"Bakkenist","year":"2003","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/35043058","article-title":"The many substrates and functions of ATM","volume":"1","author":"Kastan","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2014.06.034","article-title":"DNA damage and its links to neurodegeneration","volume":"83","author":"Madabhushi","year":"2014","journal-title":"Neuron"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e54217","DOI":"10.15252\/embr.202154217","article-title":"Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease","volume":"23","author":"Welch","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molbrainres.2004.05.023","article-title":"Deficiency of the Mre11 DNA repair complex in Alzheimer\u2019s disease brains","volume":"128","author":"Jacobsen","year":"2004","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"7497","DOI":"10.1093\/nar\/gkm821","article-title":"Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer\u2019s disease","volume":"35","author":"Lovell","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nature02661","article-title":"Gene regulation and DNA damage in the ageing human brain","volume":"429","author":"Lu","year":"2004","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s40478-019-0723-5","article-title":"Early neuronal accumulation of DNA double strand breaks in Alzheimer\u2019s disease","volume":"7","author":"Shanbhag","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41586-024-07220-7","article-title":"Formation of memory assemblies through the DNA-sensing TLR9 pathway","volume":"628","author":"Jovasevic","year":"2024","journal-title":"Nature"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0006-8993(99)02004-1","article-title":"DNA strand breaks in Alzheimer\u2019s disease","volume":"849","author":"Adamec","year":"1999","journal-title":"Brain Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1523\/ENEURO.0124-15.2016","article-title":"Neurons in Vulnerable Regions of the Alzheimer\u2019s Disease Brain Display Reduced ATM Signaling","volume":"3","author":"Shen","year":"2016","journal-title":"eNeuro"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1016\/j.stem.2021.04.004","article-title":"Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer\u2019s patients","volume":"28","author":"Mertens","year":"2021","journal-title":"Cell Stem Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11353\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:17:45Z","timestamp":1760113065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11353"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,22]]},"references-count":94,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111353"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111353","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,22]]}}}