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 [SE] Hjärnfonden [SE] Gun and Bertil Stohne’s foundation [SE] Alzheimerfonden [SE]
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.
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