Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy.
Mitra, Sumonto; Turchetto, Silvia; Van Os, Winantet al.
[en] Alzheimer's disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood-brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery in AD patients but was found to have reduced hmNGF release over time. To understand the reason behind reduced ECB efficacy, we exposed hmNGF-releasing cells (NGC0211) in vitro to human cerebrospinal fluid (CSF) obtained from Subjective Cognitive Impairment (SCI), Lewy Body Dementia (LBD), and AD patients. Subsequently, we exposed NGC0211 cells directly to AD-related factors like amyloid-β peptides (Aβ40/42) or activated astrocyte-conditioned medium (Aβ40/42/IL-1β/TNFα-treated) and evaluated biochemical stress markers, cell death indicators, cell proliferation marker (Ki67), and hmNGF release. We found that all patients' CSF significantly reduced hmNGF release from NGC0211 cells in vitro. Aβ40/42, inflammatory molecules, and activated astrocytes significantly affected NGC0211 cell proliferation without altering hmNGF release or other parameters important for essential functions of the NGC0211 cells. Long-term constant cell proliferation within the ECB device is critically important to maintain a steady cell population needed for stable mNGF release. These data show hampered proliferation of NGC0211 cells, which may lead to a decline of the NGC0211 cell population in ECBs, thereby reducing hmNGF release. Our study highlights the need for future studies to strengthen ECB-mediated long-term drug delivery approaches.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Mitra, Sumonto ; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 141 52 Stockholm, Sweden
Turchetto, Silvia ; Université de Liège - ULiège > GIGA ; Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 171 64 Stockholm, Sweden
Van Os, Winant; Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 171 64 Stockholm, Sweden ; Wiskunde en Natuurwetenschappen, LIC/Chemical Biology, Leiden Institute of Chemistry, 2300 RA Leiden, The Netherlands
Wahlberg, Lars U; Gloriana Therapeutics, Inc., Warren, Rhode Island, RI 02885, USA
Linderoth, Bengt; Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
Behbahani, Homira; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 141 52 Stockholm, Sweden ; Karolinska University Laboratories, Karolinska University Hospital, 184 50 Stockholm, Sweden
Eriksdotter, Maria; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 141 52 Stockholm, Sweden ; Theme Aging, Karolinska University Hospital, 141 86 Huddinge, Sweden
Language :
English
Title :
Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy.
Swedish Research Council Hjärnfonden Gun and Bertil Stohne’s foundation Alzheimerfonden
Funding text :
Funding: This research was supported by the Swedish research council (2016-02317), Hjärnfonden, Demensfonden, Lindhés stiftelse, Gun and Bertil Stohne’s Foundation (20200917), Gamla Tjänarinnor stiftelse (2019-00846), Åhlen stiftelse, Alzheimerfonden, Tore Nilsson stiftelse, KI Geriatric research, KI fund and ALF Foundation for medicine. We want to thank Alzheimer Nederland for financially supporting the International Research Internship of W.V.O., encouraging international collaborations.This research was supported by the Swedish research council (2016-02317), Hj?rnfonden, Demensfonden, Lindh?s stiftelse, Gun and Bertil Stohne?s Foundation (20200917), Gamla Tj?narinnor stiftelse (2019-00846), ?hlen stiftelse, Alzheimerfonden, Tore Nilsson stiftelse, KI Geriatric research, KI fund and ALF Foundation for medicine. We want to thank Alzheimer Nederland for financially supporting the International Research Internship of W.V.O., encouraging international collaborations.
Cuello, A.C.; Pentz, R.; Hall, H. The brain NGF metabolic pathway in health and in Alzheimer’s pathology. Front. Neurosci. 2019, 13, 62. [CrossRef]
Teipel, S.J.; Cavedo, E.; Hampel, H.; Grothe, M.J. Basal forebrain volume, but not hippocampal volume, is a predictor of global cognitive decline in patients with Alzheimer’s disease treated with cholinesterase inhibitors. Front. Neurol. 2018, 9, 642. [CrossRef] [PubMed]
Aloe, L.; Rocco, M.L.; Balzamino, B.O.; Micera, A. Nerve growth factor: A focus on neuroscience and therapy. Curr. Neuropharmacol. 2015, 13, 294–303. [CrossRef]
Cuello, A.C.; Bruno, M.A.; Allard, S.; Leon, W.; Iulita, M.F. Cholinergic involvement in Alzheimer’s disease. A link with NGF maturation and degradation. J. Mol. Neurosci. 2010, 40, 230–235. [CrossRef]
Peng, S.; Wuu, J.; Mufson, E.J.; Fahnestock, M. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J. Neuropathol. Exp. Neurol. 2004, 63, 641–649. [CrossRef] [PubMed]
Song, W.; Volosin, M.; Cragnolini, A.B.; Hempstead, B.L.; Friedman, W.J. ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J. Neurosci. 2010, 30, 15608–15615. [CrossRef] [PubMed]
Ginsberg, S.D.; Che, S.; Wuu, J.; Counts, S.E.; Mufson, E.J. Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. J. Neurochem. 2006, 97, 475–487. [CrossRef]
Sanchez-Ortiz, E.; Yui, D.; Song, D.; Li, Y.; Rubenstein, J.L.; Reichardt, L.F.; Parada, L.F. TrkA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry. J. Neurosci. 2012, 32, 4065–4079. [CrossRef]
Haam, J.; Yakel, J.L. Cholinergic modulation of the hippocampal region and memory function. J. Neurochem. 2017, 142 (Suppl. 2), 111–121. [CrossRef]
Ballinger, E.C.; Ananth, M.; Talmage, D.A.; Role, L.W. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron 2016, 91, 1199–1218. [CrossRef]
Hasselmo, M.E.; Sarter, M. Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology 2011, 36, 52–73. [CrossRef] [PubMed]
Mitra, S.; Behbahani, H.; Eriksdotter, M. Innovative therapy for Alzheimer’s disease-with focus on biodelivery of NGF. Front. Neurosci. 2019, 13, 38. [CrossRef]
Wahlberg, L.U.; Lind, G.; Almqvist, P.M.; Kusk, P.; Tornoe, J.; Juliusson, B.; Soderman, M.; Sellden, E.; Seiger, A.; Eriksdotter-Jonhagen, M.; et al. Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: A technology platform for restorative neurosurgery. J. Neurosurg. 2012, 117, 340–347. [CrossRef]
Eriksdotter-Jonhagen, M.; Linderoth, B.; Lind, G.; Aladellie, L.; Almkvist, O.; Andreasen, N.; Blennow, K.; Bogdanovic, N.; Jelic, V.; Kadir, A.; et al. Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 2012, 33, 18–28. [CrossRef] [PubMed]
Eyjolfsdottir, H.; Eriksdotter, M.; Linderoth, B.; Lind, G.; Juliusson, B.; Kusk, P.; Almkvist, O.; Andreasen, N.; Blennow, K.; Ferreira, D.; et al. Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer’s disease patients: Application of a second-generation encapsulated cell biodelivery device. Alzheimers Res. Ther. 2016, 8, 30. [CrossRef] [PubMed]
Fjord-Larsen, L.; Kusk, P.; Emerich, D.F.; Thanos, C.; Torp, M.; Bintz, B.; Tornoe, J.; Johnsen, A.H.; Wahlberg, L.U. Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer. Gene. Ther. 2012, 19, 1010–1017. [CrossRef] [PubMed]
Kauppinen, A.; Paterno, J.J.; Blasiak, J.; Salminen, A.; Kaarniranta, K. Inflammation and its role in age-related macular degenera-tion. Cell Mol. Life Sci. 2016, 73, 1765–1786. [CrossRef]
Saxena, S.; Maze, M. Impact on the brain of the inflammatory response to surgery. Presse. Med. 2018, 47, e73–e81. [CrossRef]
Eriksdotter, M.; Navarro-Oviedo, M.; Mitra, S.; Wahlberg, L.; Linderoth, B.; Tjernberg, L.O.; Behbahani, H. Cerebrospinal fluid from Alzheimer patients affects cell-mediated nerve growth factor production and cell survival in vitro. Exp. Cell Res. 2018, 371, 175–184. [CrossRef]
Stine, W.B.; Jungbauer, L.; Yu, C.; LaDu, M.J. Preparing synthetic Abeta in different aggregation states. Methods Mol. Biol. 2011, 670, 13–32. [CrossRef]
Wicklund, L.; Leao, R.N.; Stromberg, A.M.; Mousavi, M.; Hovatta, O.; Nordberg, A.; Marutle, A. Beta-amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic neurons. PLoS ONE 2010, 5, e15600. [CrossRef] [PubMed]
Darreh-Shori, T.; Rezaeianyazdi, S.; Lana, E.; Mitra, S.; Gellerbring, A.; Karami, A.; Bogdanovic, N.; Lithner, C.U.; Winblad, B.; Behbahani, H. Increased active OMI/HTRA2 serine protease displays a positive correlation with cholinergic alterations in the Alzheimer’s disease brain. Mol. Neurobiol. 2019, 56, 4601–4619. [CrossRef] [PubMed]
Hoitzing, H.; Johnston, I.G.; Jones, N.S. What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research. Bioessays 2015, 37, 687–700. [CrossRef] [PubMed]
Lai, A.Y.; McLaurin, J. Mechanisms of amyloid-Beta peptide uptake by neurons: The role of lipid rafts and lipid raft-associated proteins. Int. J. Alzheimer’s Dis. 2010, 2011, 548380. [CrossRef]
Roher, A.E.; Esh, C.L.; Kokjohn, T.A.; Castano, E.M.; Van Vickle, G.D.; Kalback, W.M.; Patton, R.L.; Luehrs, D.C.; Daugs, I.D.; Kuo, Y.M.; et al. Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimer’s Dement. 2009, 5, 18–29. [CrossRef]
Collins-Praino, L.E.; Francis, Y.I.; Griffith, E.Y.; Wiegman, A.F.; Urbach, J.; Lawton, A.; Honig, L.S.; Cortes, E.; Vonsattel, J.P.; Canoll, P.D.; et al. Soluble amyloid beta levels are elevated in the white matter of Alzheimer’s patients, independent of cortical plaque severity. Acta Neuropathol. Commun. 2014, 2, 83. [CrossRef]
Takahashi, R.H.; Nam, E.E.; Edgar, M.; Gouras, G.K. Alzheimer beta-amyloid peptides: Normal and abnormal localization. Histol. Histopathol. 2002, 17, 239–246. [CrossRef]
Liu, R.T.; Gao, J.; Cao, S.; Sandhu, N.; Cui, J.Z.; Chou, C.L.; Fang, E.; Matsubara, J.A. Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: Implications for inflammasome activation in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013, 54, 2225–2237. [CrossRef]
Mitra, S.; Prasad, P.; Chakraborty, S. A unified view of assessing the pro-oxidant versus antioxidant nature of amyloid beta conformers. Chembiochem 2018, 19, 2360–2371. [CrossRef] [PubMed]
Zou, K.; Gong, J.S.; Yanagisawa, K.; Michikawa, M. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J. Neurosci. 2002, 22, 4833–4841. [CrossRef] [PubMed]
Cao, S.; Walker, G.B.; Wang, X.; Cui, J.Z.; Matsubara, J.A. Altered cytokine profiles of human retinal pigment epithelium: Oxidant injury and replicative senescence. Mol. Vis. 2013, 19, 718–728.
Li, Y.; Frei, A.W.; Yang, E.Y.; Labrada-Miravet, I.; Sun, C.; Rong, Y.; Samojlik, M.M.; Bayer, A.L.; Stabler, C.L. In vitro platform establishes antigen-specific CD8(+) T cell cytotoxicity to encapsulated cells via indirect antigen recognition. Biomaterials 2020, 256, 120182. [CrossRef] [PubMed]
Harris, M.G.; Hulseberg, P.; Ling, C.; Karman, J.; Clarkson, B.D.; Harding, J.S.; Zhang, M.; Sandor, A.; Christensen, K.; Nagy, A.; et al. Immune privilege of the CNS is not the consequence of limited antigen sampling. Sci. Rep. 2014, 4, 4422. [CrossRef] [PubMed]
Szatmari-Toth, M.; Kristof, E.; Vereb, Z.; Akhtar, S.; Facsko, A.; Fesus, L.; Kauppinen, A.; Kaarniranta, K.; Petrovski, G. Clearance of autophagy-associated dying retinal pigment epithelial cells—A possible source for inflammation in age-related macular degeneration. Cell Death Dis. 2016, 7, e2367. [CrossRef]
Inana, G.; Murat, C.; An, W.; Yao, X.; Harris, I.R.; Cao, J. RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells. J. Transl. Med. 2018, 16, 63. [CrossRef]
Ishii, M.; Rohrer, B. Mechanisms of bystander effects in retinal pigment epithelium cell networks. Cell Death Dis. 2017, 8, e3061. [CrossRef] [PubMed]
Fan, Y.; Bergmann, A. Apoptosis-induced compensatory proliferation. The Cell is dead. Long live the Cell! Trends Cell Biol. 2008, 18, 467–473. [CrossRef]
Goss, J.R.; O’Malley, M.E.; Zou, L.; Styren, S.D.; Kochanek, P.M.; DeKosky, S.T. Astrocytes are the major source of nerve growth factor upregulation following traumatic brain injury in the rat. Exp. Neurol. 1998, 149, 301–309. [CrossRef]
Paolone, G.; Falcicchia, C.; Lovisari, F.; Kokaia, M.; Bell, W.J.; Fradet, T.; Barbieri, M.; Wahlberg, L.U.; Emerich, D.F.; Simonato, M. Long-term, targeted delivery of GDNF from encapsulated cells is neuroprotective and reduces seizures in the pilocarpine model of epilepsy. J. Neurosci. 2019, 39, 2144–2156. [CrossRef]
Falcicchia, C.; Paolone, G.; Emerich, D.F.; Lovisari, F.; Bell, W.J.; Fradet, T.; Wahlberg, L.U.; Simonato, M. Seizure-suppressant and neuroprotective effects of encapsulated bdnf-producing cells in a rat model of temporal lobe epilepsy. Mol. Ther. Methods Clin. Dev. 2018, 9, 211–224. [CrossRef]
Jorgensen, J.R.; Xu, X.J.; Arnold, H.M.; Munro, G.; Hao, J.X.; Pepinsky, B.; Huang, C.; Gong, B.J.; Wiesenfeld-Hallin, Z.; Wahlberg, L.U.; et al. Meteorin reverses hypersensitivity in rat models of neuropathic pain. Exp. Neurol. 2012, 237, 260–266. [CrossRef]
Jorgensen, J.R.; Fransson, A.; Fjord-Larsen, L.; Thompson, L.H.; Houchins, J.P.; Andrade, N.; Torp, M.; Kalkkinen, N.; Anders-son, E.; Lindvall, O.; et al. Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Exp. Neurol. 2012, 233, 172–181. [CrossRef]
Yoshida, T.; Ohno-Matsui, K.; Ichinose, S.; Sato, T.; Iwata, N.; Saido, T.C.; Hisatomi, T.; Mochizuki, M.; Morita, I. The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. J. Clin. Investig. 2005, 115, 2793–2800. [CrossRef] [PubMed]
Gonzalez-Reyes, R.E.; Nava-Mesa, M.O.; Vargas-Sanchez, K.; Ariza-Salamanca, D.; Mora-Munoz, L. Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective. Front. Mol. Neurosci. 2017, 10, 427. [CrossRef] [PubMed]
Wyssenbach, A.; Quintela, T.; Llavero, F.; Zugaza, J.L.; Matute, C.; Alberdi, E. Amyloid beta-induced astrogliosis is mediated by beta1-integrin via NADPH oxidase 2 in Alzheimer’s disease. Aging Cell 2016, 15, 1140–1152. [CrossRef] [PubMed]
