Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy
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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/10/11/2834 |
| _version_ | 1797510898270601216 |
|---|---|
| author | Sumonto Mitra Silvia Turchetto Winant Van Os Lars U. Wahlberg Bengt Linderoth Homira Behbahani Maria Eriksdotter |
| author_facet | Sumonto Mitra Silvia Turchetto Winant Van Os Lars U. Wahlberg Bengt Linderoth Homira Behbahani Maria Eriksdotter |
| author_sort | Sumonto Mitra |
| collection | DOAJ |
| description | 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 (Aβ<sub>40/42</sub>) or activated astrocyte-conditioned medium (Aβ<sub>40/42</sub>/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. Aβ<sub>40/42</sub>, 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. |
| first_indexed | 2024-03-10T05:37:50Z |
| format | Article |
| id | doaj.art-e39d600451674b41b865b11435764563 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:37:50Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e39d600451674b41b865b114357645632023-11-22T22:47:25ZengMDPI AGCells2073-44092021-10-011011283410.3390/cells10112834Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD TherapySumonto Mitra0Silvia Turchetto1Winant Van Os2Lars U. Wahlberg3Bengt Linderoth4Homira Behbahani5Maria Eriksdotter6Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 141 52 Stockholm, SwedenDivision of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 171 64 Stockholm, SwedenDivision of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 171 64 Stockholm, SwedenGloriana Therapeutics, Inc., Warren, Rhode Island, RI 02885, USADepartment of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 141 52 Stockholm, SwedenDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 141 52 Stockholm, SwedenAlzheimer’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 (Aβ<sub>40/42</sub>) or activated astrocyte-conditioned medium (Aβ<sub>40/42</sub>/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. Aβ<sub>40/42</sub>, 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.https://www.mdpi.com/2073-4409/10/11/2834Alzheimer’s disease (AD)astrocytesamyloid beta (Aβ)encapsulated cell biodelivery (ECB)nerve growth factor (NGF)drug delivery strategy optimization |
| spellingShingle | Sumonto Mitra Silvia Turchetto Winant Van Os Lars U. Wahlberg Bengt Linderoth Homira Behbahani Maria Eriksdotter Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy Cells Alzheimer’s disease (AD) astrocytes amyloid beta (Aβ) encapsulated cell biodelivery (ECB) nerve growth factor (NGF) drug delivery strategy optimization |
| 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 |
| title_full | Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy |
| title_fullStr | Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy |
| title_full_unstemmed | Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy |
| title_short | Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy |
| title_sort | amyloid beta peptides and activated astroglia impairs proliferation of nerve growth factor releasing cells in vitro implication for encapsulated cell biodelivery mediated ad therapy |
| topic | Alzheimer’s disease (AD) astrocytes amyloid beta (Aβ) encapsulated cell biodelivery (ECB) nerve growth factor (NGF) drug delivery strategy optimization |
| url | https://www.mdpi.com/2073-4409/10/11/2834 |
| work_keys_str_mv | AT sumontomitra amyloidbetapeptidesandactivatedastrogliaimpairsproliferationofnervegrowthfactorreleasingcellsinvitroimplicationforencapsulatedcellbiodeliverymediatedadtherapy AT silviaturchetto amyloidbetapeptidesandactivatedastrogliaimpairsproliferationofnervegrowthfactorreleasingcellsinvitroimplicationforencapsulatedcellbiodeliverymediatedadtherapy AT winantvanos amyloidbetapeptidesandactivatedastrogliaimpairsproliferationofnervegrowthfactorreleasingcellsinvitroimplicationforencapsulatedcellbiodeliverymediatedadtherapy AT larsuwahlberg amyloidbetapeptidesandactivatedastrogliaimpairsproliferationofnervegrowthfactorreleasingcellsinvitroimplicationforencapsulatedcellbiodeliverymediatedadtherapy AT bengtlinderoth amyloidbetapeptidesandactivatedastrogliaimpairsproliferationofnervegrowthfactorreleasingcellsinvitroimplicationforencapsulatedcellbiodeliverymediatedadtherapy AT homirabehbahani amyloidbetapeptidesandactivatedastrogliaimpairsproliferationofnervegrowthfactorreleasingcellsinvitroimplicationforencapsulatedcellbiodeliverymediatedadtherapy AT mariaeriksdotter amyloidbetapeptidesandactivatedastrogliaimpairsproliferationofnervegrowthfactorreleasingcellsinvitroimplicationforencapsulatedcellbiodeliverymediatedadtherapy |