Microglial regulation of neuronal activity in TDP-43 neurodegeneration

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PROJECT SUMMARY Microglia, as the resident immune cells of the central nervous system, are key players in aging and neurodegenerative diseases, such as Alzheimer’s disease (AD) and AD-related dementias (ADRD). However, how microglia sense and regulate neurodegeneration remains largely unknown. TDP-43 is a DNA-binding protein that is a main component of the protein aggregates found in amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), and AD. We used inducible mouse model of TDP-43 translocation (rNLS8) that can mimic characteristic features of TDP-43 related neurodegeneration. Utilizing in vivo two- photon imaging, we have demonstrated that rNLS8 mice show neuronal hyperactivity in the cortex during disease progression, which is associated with unique rod-shaped microglia aligning along neuronal dendrites in the layer 4 cortex. Based on these exciting observations, we hypothesize that microglia have neuroprotective roles by regulating cortical microcircuit and attenuating neuronal hyperactivity in response to TDP-43 related neurodegeneration. We will test this hypothesis with the following three Aims: Aim 1: Determine the functional heterogeneity of microglial activation in TDP-43 neurodegeneration. We will use chronic, in vivo two-photon imaging to determine the spatiotemporal activation of microglia, including process dynamics, landscape changes, and proliferation. In addition, we will examine microglial Ca2+ activity using a newly developed microglial GCaMP7s mouse line and TREM2 dependence. The results from this aim will uncover microglial heterogeneity in different phases of TDP-43 related neurodegeneration. Aim 2: Investigate how microglia regulate cortical microcircuits in TDP-43 neurodegeneration. We will study microglia-neuron interactions in different cortical layers during disease progression and recovery in rNLS8 mice using simultaneous two-photon and electron microscopy. We will also determine how microglial TREM2 regulates neuronal circuits, particularly during the early phases of disease progress, in TDP-43 related neurodegeneration. Aim 3: Manipulate microglia as a potential therapeutic target in TDP-43 neurodegeneration. We will precisely control microglial function using chemogenetics in the different phases of disease and delineate microglial contributions. In addition, we will target TREM2 for treatment of TDP-43 related neurodegeneration. Our group is perfectly poised to exploit novel methods of imaging microglia-neuron interactions and study their precise function in aging and TDP-43 related neurodegeneration like ALS, FTLD and AD. These innovative approaches will provide transformative insights into microglial mechanisms of regulating TDP-43 related neurodegeneration and spawn putative therapeutic targets that will ultimately help patients with ALS, FTLD, AD, and ADRD.