A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes
Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stim...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123002115 |
| _version_ | 1827878448282992640 |
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| author | Tarun N. Bhatia Anuj S. Jamenis Muslim Abbas Rachel N. Clark Kristin M. Miner Manisha N. Chandwani Roxanne E. Kim William Hilinski Lauren A. O'Donnell Kelvin C. Luk Yejie Shi Xiaoming Hu Jun Chen Jeffrey L. Brodsky Rehana K. Leak |
| author_facet | Tarun N. Bhatia Anuj S. Jamenis Muslim Abbas Rachel N. Clark Kristin M. Miner Manisha N. Chandwani Roxanne E. Kim William Hilinski Lauren A. O'Donnell Kelvin C. Luk Yejie Shi Xiaoming Hu Jun Chen Jeffrey L. Brodsky Rehana K. Leak |
| author_sort | Tarun N. Bhatia |
| collection | DOAJ |
| description | Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein+ inclusions in the limbic rhinencephalon after PFFs were injected in the posterior olfactory bulb. However, aged females displayed larger inclusion sizes compared to males. Short-term (14-day) dietary exposure to PLX5622 followed by control chow reduced inclusion numbers and levels of insoluble α-synuclein in aged males—but not females—and unexpectedly raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice, as evidenced by an increase in novel arm entries in a Y-maze. Superior memory was positively correlated with inclusion sizes but negatively correlated with inclusion numbers. Although we caution that PLX5622 delivery must be tested further in models of α-synucleinopathy, our data suggest that larger-sized—but fewer—α-synucleinopathic structures are associated with better neurological outcomes in PFF-infused aged mice. |
| first_indexed | 2024-03-12T17:51:43Z |
| format | Article |
| id | doaj.art-9721d7f26b7b4036901bb4feac886942 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-03-12T17:51:43Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-9721d7f26b7b4036901bb4feac8869422023-08-03T04:22:44ZengElsevierNeurobiology of Disease1095-953X2023-08-01184106196A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexesTarun N. Bhatia0Anuj S. Jamenis1Muslim Abbas2Rachel N. Clark3Kristin M. Miner4Manisha N. Chandwani5Roxanne E. Kim6William Hilinski7Lauren A. O'Donnell8Kelvin C. Luk9Yejie Shi10Xiaoming Hu11Jun Chen12Jeffrey L. Brodsky13Rehana K. Leak14Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USAB&B Microscopes, Olympus Corporation, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USADept. of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USAGeriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA; Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAGeriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA; Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAGeriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA; Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADept. of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA; Corresponding author at: Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave, Pittsburgh, PA 15282, USA.Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein+ inclusions in the limbic rhinencephalon after PFFs were injected in the posterior olfactory bulb. However, aged females displayed larger inclusion sizes compared to males. Short-term (14-day) dietary exposure to PLX5622 followed by control chow reduced inclusion numbers and levels of insoluble α-synuclein in aged males—but not females—and unexpectedly raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice, as evidenced by an increase in novel arm entries in a Y-maze. Superior memory was positively correlated with inclusion sizes but negatively correlated with inclusion numbers. Although we caution that PLX5622 delivery must be tested further in models of α-synucleinopathy, our data suggest that larger-sized—but fewer—α-synucleinopathic structures are associated with better neurological outcomes in PFF-infused aged mice.http://www.sciencedirect.com/science/article/pii/S0969996123002115MicrogliaLewy bodySynucleinDementiaNeurodegenerationParkinson's disease |
| spellingShingle | Tarun N. Bhatia Anuj S. Jamenis Muslim Abbas Rachel N. Clark Kristin M. Miner Manisha N. Chandwani Roxanne E. Kim William Hilinski Lauren A. O'Donnell Kelvin C. Luk Yejie Shi Xiaoming Hu Jun Chen Jeffrey L. Brodsky Rehana K. Leak A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes Neurobiology of Disease Microglia Lewy body Synuclein Dementia Neurodegeneration Parkinson's disease |
| title | A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes |
| title_full | A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes |
| title_fullStr | A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes |
| title_full_unstemmed | A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes |
| title_short | A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes |
| title_sort | 14 day pulse of plx5622 modifies α synucleinopathy in preformed fibril infused aged mice of both sexes |
| topic | Microglia Lewy body Synuclein Dementia Neurodegeneration Parkinson's disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123002115 |
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