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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-stimulati...

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Autores principales: Bhatia, Tarun N., Jamenis, Anuj S., Abbas, Muslim, Clark, Rachel N., Miner, Kristin M., Chandwani, Manisha N., Kim, Roxanne E., Hilinski, William, O’Donnell, Lauren A., Luk, Kelvin C., Shi, Yejie, Hu, Xiaoming, Chen, Jun, Brodsky, Jeffrey L., Leak, Rehana K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528721/
https://www.ncbi.nlm.nih.gov/pubmed/37315905
http://dx.doi.org/10.1016/j.nbd.2023.106196
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author Bhatia, Tarun N.
Jamenis, Anuj S.
Abbas, Muslim
Clark, Rachel N.
Miner, Kristin M.
Chandwani, Manisha N.
Kim, Roxanne E.
Hilinski, William
O’Donnell, Lauren A.
Luk, Kelvin C.
Shi, Yejie
Hu, Xiaoming
Chen, Jun
Brodsky, Jeffrey L.
Leak, Rehana K.
author_facet Bhatia, Tarun N.
Jamenis, Anuj S.
Abbas, Muslim
Clark, Rachel N.
Miner, Kristin M.
Chandwani, Manisha N.
Kim, Roxanne E.
Hilinski, William
O’Donnell, Lauren A.
Luk, Kelvin C.
Shi, Yejie
Hu, Xiaoming
Chen, Jun
Brodsky, Jeffrey L.
Leak, Rehana K.
author_sort Bhatia, Tarun N.
collection PubMed
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.
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spelling pubmed-105287212023-09-27 A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes Bhatia, Tarun N. Jamenis, Anuj S. Abbas, Muslim Clark, Rachel N. Miner, Kristin M. Chandwani, Manisha N. Kim, Roxanne E. Hilinski, William O’Donnell, Lauren A. Luk, Kelvin C. Shi, Yejie Hu, Xiaoming Chen, Jun Brodsky, Jeffrey L. Leak, Rehana K. Neurobiol Dis Article 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. 2023-08 2023-06-12 /pmc/articles/PMC10528721/ /pubmed/37315905 http://dx.doi.org/10.1016/j.nbd.2023.106196 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Bhatia, Tarun N.
Jamenis, Anuj S.
Abbas, Muslim
Clark, Rachel N.
Miner, Kristin M.
Chandwani, Manisha N.
Kim, Roxanne E.
Hilinski, William
O’Donnell, Lauren A.
Luk, Kelvin C.
Shi, Yejie
Hu, Xiaoming
Chen, Jun
Brodsky, Jeffrey L.
Leak, Rehana K.
A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528721/
https://www.ncbi.nlm.nih.gov/pubmed/37315905
http://dx.doi.org/10.1016/j.nbd.2023.106196
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