The Role of Microglial Lysosomes in Selective Neuronal Vulnerability

2021 Seed Grant
Linda M. De Biase, Ph.D.
University of California Los Angeles

Peter Pond Seed Grant

Synapses, the sites of signaling between neurons in the brain, play essential roles in learning, memory, and the health of neurons themselves. An enduring mystery is why some neurons are more vulnerable to synapse dysfunction, synapse loss, and neurodegenerative disease during aging. Microglia are immune-like cells that can influence synaptic function and may be critical for determining whether synapses and neurons remain healthy throughout the lifespan. We discovered that microglia in the midbrain, where vulnerable dopamine neurons reside, show different attributes from microglia in other brain regions. They can regulate dynamic changes in dopamine neuron synapse function and they “respond” to aging long before microglia in other brain regions. These early aging responses of midbrain microglia include cell proliferation and production of inflammatory factors that can be damaging to nearby synapses and neurons. Whether these regional differences in microglial features and microglial responses to aging give rise to regional differences in synapse integrity and neuronal vulnerability remains unknown. Published studies and our preliminary data suggest that cellular organelles called lysosomes may be central controllers of regional differences in microglial attributes and responses to aging. A key challenge for study of microglia is that microglia are more difficult to manipulate genetically than other brain cells. In this proposal, we will develop new approaches for genetic modification of microglia that will allow us to selectively alter multiple aspects of microglial lysosome function. We will define how these changes in microglial lysosome function impact synapse-relevant microglial attributes and synaptic function of nearby neurons. This work promises to uncover key factors that regulate synapse-relevant attributes of microglia throughout the lifespan and to reveal new strategies for protecting vulnerable populations of neurons.

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