Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloid
Abstract Alzheimer's disease (AD) is characterized by beta‐amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-03-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13095 |
| _version_ | 1797261346023145472 |
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| author | Catherine Weathered Sophia Bardehle Choya Yoon Niyanta Kumar Cheryl E. G. Leyns Matthew E. Kennedy Peter Bloomingdale Elsje Pienaar |
| author_facet | Catherine Weathered Sophia Bardehle Choya Yoon Niyanta Kumar Cheryl E. G. Leyns Matthew E. Kennedy Peter Bloomingdale Elsje Pienaar |
| author_sort | Catherine Weathered |
| collection | DOAJ |
| description | Abstract Alzheimer's disease (AD) is characterized by beta‐amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia are innate phagocytotic immune cells that transition into a neuroprotective state and form barriers around plaques. We seek to understand the role of microglia in modifying Aβ dynamics and barrier formation. To quantify the influence of individual microglia behaviors (activation, chemotaxis, phagocytosis, and proliferation) on plaque size and barrier coverage, we developed an agent‐based model to characterize the spatiotemporal interactions between microglia and Aβ. Our model qualitatively reproduces mouse data trends where the fraction of microglia coverage decreases as plaques become larger. In our model, the time to microglial arrival at the plaque boundary is significantly negatively correlated (p < 0.0001) with plaque size, indicating the importance of the time to microglial activation for regulating plaque size. In addition, in silico behavioral knockout simulations show that phagocytosis knockouts have the strongest impact on plaque size, but modest impacts on microglial coverage and activation. In contrast, the chemotaxis knockouts had a strong impact on microglial coverage with a more modest impact on plaque volume and microglial activation. These simulations suggest that phagocytosis, chemotaxis, and replication of activated microglia have complex impacts on plaque volume and coverage, whereas microglial activation remains fairly robust to perturbations of these functions. Thus, our work provides insights into the potential and limitations of targeting microglial activation as a pharmacological strategy for the treatment of AD. |
| first_indexed | 2024-04-24T23:39:45Z |
| format | Article |
| id | doaj.art-15e39054b039415a96117e3e3217cfcb |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-04-24T23:39:45Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-15e39054b039415a96117e3e3217cfcb2024-03-15T12:48:49ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062024-03-0113344946310.1002/psp4.13095Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloidCatherine Weathered0Sophia Bardehle1Choya Yoon2Niyanta Kumar3Cheryl E. G. Leyns4Matthew E. Kennedy5Peter Bloomingdale6Elsje Pienaar7Weldon School of Biomedical Engineering Purdue University West Lafayette Indiana USANeuroimmunology Merck & Co., Inc. Rahway New Jersey USANeuroimmunology Merck & Co., Inc. Rahway New Jersey USAPharmacokinetics and Pharmacodynamics Merck & Co., Inc. Rahway New Jersey USANeuroimmunology Merck & Co., Inc. Rahway New Jersey USANeuroscience Merck & Co., Inc. Rahway New Jersey USAQuantitative Pharmacology and Pharmacometrics Merck & Co., Inc. Rahway New Jersey USAWeldon School of Biomedical Engineering Purdue University West Lafayette Indiana USAAbstract Alzheimer's disease (AD) is characterized by beta‐amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia are innate phagocytotic immune cells that transition into a neuroprotective state and form barriers around plaques. We seek to understand the role of microglia in modifying Aβ dynamics and barrier formation. To quantify the influence of individual microglia behaviors (activation, chemotaxis, phagocytosis, and proliferation) on plaque size and barrier coverage, we developed an agent‐based model to characterize the spatiotemporal interactions between microglia and Aβ. Our model qualitatively reproduces mouse data trends where the fraction of microglia coverage decreases as plaques become larger. In our model, the time to microglial arrival at the plaque boundary is significantly negatively correlated (p < 0.0001) with plaque size, indicating the importance of the time to microglial activation for regulating plaque size. In addition, in silico behavioral knockout simulations show that phagocytosis knockouts have the strongest impact on plaque size, but modest impacts on microglial coverage and activation. In contrast, the chemotaxis knockouts had a strong impact on microglial coverage with a more modest impact on plaque volume and microglial activation. These simulations suggest that phagocytosis, chemotaxis, and replication of activated microglia have complex impacts on plaque volume and coverage, whereas microglial activation remains fairly robust to perturbations of these functions. Thus, our work provides insights into the potential and limitations of targeting microglial activation as a pharmacological strategy for the treatment of AD.https://doi.org/10.1002/psp4.13095 |
| spellingShingle | Catherine Weathered Sophia Bardehle Choya Yoon Niyanta Kumar Cheryl E. G. Leyns Matthew E. Kennedy Peter Bloomingdale Elsje Pienaar Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloid CPT: Pharmacometrics & Systems Pharmacology |
| title | Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloid |
| title_full | Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloid |
| title_fullStr | Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloid |
| title_full_unstemmed | Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloid |
| title_short | Microglial roles in Alzheimer's disease: An agent‐based model to elucidate microglial spatiotemporal response to beta‐amyloid |
| title_sort | microglial roles in alzheimer s disease an agent based model to elucidate microglial spatiotemporal response to beta amyloid |
| url | https://doi.org/10.1002/psp4.13095 |
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