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Microglial regulation of neuronal activity in TDP-43 neurodegeneration

Award Number: R01AG082314
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Microglial regulation of neuronal activity in TDP-43 neurodegeneration - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $711,702 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	3	4/9/2026	EXTENSION WITH OR WITHOUT FUNDS	$711,702
														Subtotal = $711,702

Grand Total All Awards = $711,702

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Microglial regulation of neuronal activity in TDP-43 neurodegeneration

Award Number: R01AG082314

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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