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Research Articles, Cellular/Molecular

Microglia Drive Pockets of Neuroinflammation in Middle Age

Eric N. Moca, Daniela Lecca, Keenan T. Hope, Fanny Etienne, Ari W. Schaler, Katherine Espinoza, Megan S. Chappell, Daniel T. Gray, David Tweedie, Shanaya Sidhu, Lindsay Masukawa, Hannah Sitoy, Rose Mathew, Daniel R. Saban, Nigel H. Greig and Lindsay M. De Biase
Journal of Neuroscience 11 May 2022, 42 (19) 3896-3918; DOI: https://doi.org/10.1523/JNEUROSCI.1922-21.2022
Eric N. Moca
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Daniela Lecca
2Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224
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Keenan T. Hope
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Fanny Etienne
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Ari W. Schaler
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Katherine Espinoza
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Megan S. Chappell
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Daniel T. Gray
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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David Tweedie
2Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224
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Shanaya Sidhu
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Lindsay Masukawa
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Hannah Sitoy
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Rose Mathew
3Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina 27710
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Daniel R. Saban
3Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina 27710
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Nigel H. Greig
2Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224
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Lindsay M. De Biase
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
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Abstract

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging.

SIGNIFICANCE STATEMENT Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.

  • aging
  • basal ganglia
  • dopamine neuron
  • inflammation
  • lysosome
  • microglia

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The Journal of Neuroscience: 42 (19)
Journal of Neuroscience
Vol. 42, Issue 19
11 May 2022
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Microglia Drive Pockets of Neuroinflammation in Middle Age
Eric N. Moca, Daniela Lecca, Keenan T. Hope, Fanny Etienne, Ari W. Schaler, Katherine Espinoza, Megan S. Chappell, Daniel T. Gray, David Tweedie, Shanaya Sidhu, Lindsay Masukawa, Hannah Sitoy, Rose Mathew, Daniel R. Saban, Nigel H. Greig, Lindsay M. De Biase
Journal of Neuroscience 11 May 2022, 42 (19) 3896-3918; DOI: 10.1523/JNEUROSCI.1922-21.2022

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Microglia Drive Pockets of Neuroinflammation in Middle Age
Eric N. Moca, Daniela Lecca, Keenan T. Hope, Fanny Etienne, Ari W. Schaler, Katherine Espinoza, Megan S. Chappell, Daniel T. Gray, David Tweedie, Shanaya Sidhu, Lindsay Masukawa, Hannah Sitoy, Rose Mathew, Daniel R. Saban, Nigel H. Greig, Lindsay M. De Biase
Journal of Neuroscience 11 May 2022, 42 (19) 3896-3918; DOI: 10.1523/JNEUROSCI.1922-21.2022
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Keywords

  • aging
  • basal ganglia
  • dopamine neuron
  • inflammation
  • lysosome
  • microglia

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