{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T11:54:40Z","timestamp":1782129280537,"version":"3.54.5"},"reference-count":103,"publisher":"SAGE Publications","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,11,9]]},"abstract":"<jats:p>Background: A significant subset of patients with Alzheimer\u2019s disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons\u2014which densely innervate bone and potently modulate bone remodeling\u2014is implicated in this pathological bone reformation. Objective: Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs). Methods: Toward this end, activated SN-like PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-\u03b1) under mono- and co-culture conditions. Results: PC12s and MSCs exposed separately to TNF-\u03b1 displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-\u03b1 was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-\u03b1-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-\u03b1 stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-\u03b1 stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain. Conclusion: Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss.<\/jats:p>","DOI":"10.3233\/jad-215007","type":"journal-article","created":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T12:38:12Z","timestamp":1632487092000},"page":"647-658","source":"Crossref","is-referenced-by-count":5,"title":["Modeling Sympathetic Hyperactivity in Alzheimer\u2019s Related Bone Loss"],"prefix":"10.1177","volume":"84","author":[{"given":"Robert A.","family":"Culibrk","sequence":"first","affiliation":[{"name":"Hahn Tissue Lab, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad S.","family":"Arabiyat","sequence":"additional","affiliation":[{"name":"Hahn Tissue Lab, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carisa 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pathway","volume":"12","author":"Yu","year":"2019","journal-title":"Int J Clin Exp Med"},{"key":"10.3233\/JAD-215007_ref3","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.3233\/JAD-160658","article-title":"Early Evidence of low bone density and decreased serotonergic synthesis in the dorsal raphe of a tauopathy model of Alzheimer\u2019s disease","volume":"55","author":"Dengler-Crish","year":"2017","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-215007_ref4","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.neurobiolaging.2018.03.021","article-title":"Evidence of Wnt\/\u03b2-catenin alterations in brain and bone of a tauopathy mouse model of Alzheimer\u2019s disease","volume":"67","author":"Dengler-Crish","year":"2018","journal-title":"Neurobiol Aging"},{"key":"10.3233\/JAD-215007_ref5","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ijge.2018.03.007","article-title":"Association between osteoporosis, bone mineral density levels and 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Chem"},{"key":"10.3233\/JAD-215007_ref12","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.bone.2013.06.002","article-title":"Chronic low dose tumor necrosis factor-\u03b1 (TNF) suppresses early bone accrual in young mice by inhibiting osteoblasts without affecting osteoclasts","volume":"56","author":"Gilbert","year":"2013","journal-title":"Bone"},{"key":"10.3233\/JAD-215007_ref13","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.cmet.2015.08.016","article-title":"Metabolic and non-cognitive manifestations of Alzheimer\u2019s disease: The hypothalamus as both culprit and target of pathology","volume":"22","author":"Ishii","year":"2015","journal-title":"Cell Metab"},{"key":"10.3233\/JAD-215007_ref14","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.biopsych.2009.04.001","article-title":"Unwind: Chronic stress exacerbates the deficits of Alzheimer\u2019s disease","volume":"65","author":"Alberini","year":"2009","journal-title":"Biol Psychiatry"},{"key":"10.3233\/JAD-215007_ref15","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1152\/physrev.00014.2017","article-title":"Impact of the autonomic nervous system on the skeleton","volume":"98","author":"Elefteriou","year":"2018","journal-title":"Physiol Rev"},{"key":"10.3233\/JAD-215007_ref16","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.neuroscience.2005.03.060","article-title":"Central autonomic control of the bone marrow: Multisynaptic tract tracing by recombinant pseudorabies virus","volume":"134","author":"D\u00e9nes","year":"2005","journal-title":"Neuroscience"},{"key":"10.3233\/JAD-215007_ref17","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0092-8674(02)01049-8","article-title":"Leptin regulates bone formation via the sympathetic nervous 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Biochem"},{"key":"10.3233\/JAD-215007_ref37","doi-asserted-by":"crossref","first-page":"583884","DOI":"10.3389\/fnagi.2020.583884","article-title":"The role of chronic inflammatory bone and joint disorders in the pathogenesis and progression of Alzheimer\u2019s disease","volume":"12","author":"Culibrk","year":"2020","journal-title":"Front Aging Neurosci"},{"key":"10.3233\/JAD-215007_ref38","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1023\/A:1020568013953","article-title":"Intracerebral production of tumor necrosis factor-\u03b1, a local neuroprotective agent, in Alzheimer disease and vascular dementia","volume":"19","author":"Tarkowski","year":"1999","journal-title":"J Clin Immunol"},{"key":"10.3233\/JAD-215007_ref39","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 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Med"},{"key":"10.3233\/JAD-215007_ref55","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.mito.2010.04.007","article-title":"S-Nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration","volume":"10","author":"Nakamura","year":"2010","journal-title":"Mitochondrion"},{"key":"10.3233\/JAD-215007_ref56","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.bbr.2010.01.040","article-title":"The role of TNF-\u03b1 signaling pathway on COX-2 upregulation and cognitive decline induced by \u03b2-amyloid peptide","volume":"209","author":"Medeiros","year":"2010","journal-title":"Behav Brain Res"},{"key":"10.3233\/JAD-215007_ref57","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1161\/HYPERTENSIONAHA.109.142836","article-title":"Brain perivascular macrophages and the sympathetic response to inflammation in rats after myocardial 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MAP kinases in lipopolysaccharide-treated PC12 Cells","volume":"26","author":"Geng","year":"2012","journal-title":"Phyther Res"},{"key":"10.3233\/JAD-215007_ref61","first-page":"478","article-title":"Ferulic acid protects pc12 neurons against hypoxia by inhibiting the p-MAPKs and COX-2 pathways","volume":"18","author":"Lin","year":"2015","journal-title":"Iran J Basic Med Sci"},{"key":"10.3233\/JAD-215007_ref62","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1021\/jf501314g","article-title":"P-coumaric acid and ursolic acid from corni fructus attenuated \u03b2-amyloid25-35-induced toxicity through regulation of the NF-\u03baB signaling pathway in PC12 cells","volume":"62","author":"Yoon","year":"2014","journal-title":"J Agric Food Chem"},{"key":"10.3233\/JAD-215007_ref63","doi-asserted-by":"crossref","first-page":"693","DOI":"10.3389\/fnins.2020.00693","article-title":"Integrated pathways of COX-2 and mTOR: Roles in cell sensing and Alzheimer\u2019s 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