Microglia Drive Pockets of Neuroinflammation in Middle Age

• DOI: 10.1523/jneurosci.1922-21.2022
• Publication Date: 2022-04-08T17:50:15Z
• Authors: 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
• Keywords: Male; Aging; 1.1 Normal biological development and functioning; dopamine neuron; microglia; Neurodegenerative; Medical and Health Sciences; Mice; Underpinning research; Acquired Cognitive Impairment; 2.1 Biological and endogenous factors; Animals; Aetiology; Neurons; Neurology & Neurosurgery; aging; Psychology and Cognitive Sciences; Neurosciences; Neurodegenerative Diseases; Brain Disorders; Good Health and Well Being; inflammation; Neurological; basal ganglia; Neuroinflammatory Diseases; Synapses; lysosome; Female; Microglia

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 STATEMENTMicroglia 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.