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Microglia contribution to disease pathogenesis in C9orf72 ALS/FTD

Award Number: R01NS120331
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Microglia contribution to disease pathogenesis in C9orf72 ALS/FTD - Project Abstract The role of microglia in the C9orf72 (C9) amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD) disease spectrum remains poorly understood. Early investigations found that microglia activation was significantly higher in ALS with dementia and impaired executive function, suggesting that microglia activation correlates with FTD-like symptoms in ALS. More recent neuropathologic examinations of microglia in FTLD patient autopsy brains with mutations in progranulin versus C9orf72 concluded that the observed microglia dysfunction was different between the two genetically different patient subgroups suggesting specificity of microglia dysfunction depending on the etiology of the patient population. One interesting aspect of microglia- neuron communication is the role of microglia in the maintenance and refinement of synaptic networks through the selective pruning of synapses, which occurs predominantly during development but has been shown to also be triggered in Alzheimer's disease (AD) and related dementias, including FTD. The degree of synapse loss in AD strongly correlates with cognitive decline, even more than the amount of plaque, tangles or neuronal loss, and a recent study of ALS postmortem tissue confirmed increased synapse loss in the prefrontal cortex of patients with reported cognitive impairments. Our laboratory has preliminary data supporting the hypothesis that there is an altered neural-immune interaction in the cortical forebrain regions of C9orf72 patients with confirmed FTD in which microglia and neurons modify each other's function. Using patient-derived hiPSC microglia and cortical neurons, we are able to show that C9 patient-derived hiPSC microglia mono-cultures do have intrinsic phenotypes, including altered gene profiles, phagocytic activities and lysosomal function. Most interestingly, preliminary data suggests that C9 microglia do regulate neuronal excitability and survival of C9 iPSC neurons. To further investigate the role and contribution of microglia in C9 cortical degeneration, we propose to thoroughly investigate the intrinsic properties of C9 hiPSC-microglia (from all patient subgroups: FTD, FTD/ALS, ALS; Aim1). For the first time, we will then co-culture these microglia with C9 and healthy control hiPSC cortical neurons to better understand the co-regulation between these two cell types (Aim 2). Finally, in the third aim, we will study microglia activation and pathology in C9 patient postmortem autopsy tissue. This will include cell-type specific genetic profiling from existing snRNA seq data sets, immunohistochemistry of microgliosis and multi-label immunostaining for microglial-specific candidate genes/proteins in conjunction with C9 neuronal disease pathology markers (TDP-43 and C9 DPRs) to gain novel knowledge on whether microglia are preferentially altered in close vicinity to neuronal pathologies.


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: 2025 ( Subtotal = $852,566 )
2025	2025	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	9/8/2025	SUPPLEMENT FOR EXPANSION	$64,322
2025	2025	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	8/18/2025	NON-COMPETING CONTINUATION	$788,244
2025	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/11/2025	NON-COMPETING CONTINUATION	$0
2025	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $852,566

Issue Date FY: 2024 ( Subtotal = $903,539 )
2024	2024	DIGNITY HEALTH	350 W THOMAS RD	PHOENIX	AZ	85013	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	8/1/2024	NON-COMPETING CONTINUATION	$811,977
2024	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/10/2024	SUPPLEMENT FOR EXPANSION	$27,240
2024	2024	DIGNITY HEALTH	350 W THOMAS RD	PHOENIX	AZ	85013	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	8/2/2024	SUPPLEMENT FOR EXPANSION	$64,322
2024	2023	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $903,539

Issue Date FY: 2023 ( Subtotal = $805,554 )
2023	2023	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/2/2023	NON-COMPETING CONTINUATION	$805,554
														Subtotal = $805,554

Issue Date FY: 2022 ( Subtotal = $831,382 )
2022	2022	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/1/2022	NON-COMPETING CONTINUATION	$831,382
														Subtotal = $831,382

Issue Date FY: 2021 ( Subtotal = $836,154 )
2021	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/30/2021	NEW	$836,154
														Subtotal = $836,154

Grand Total All Awards = $4,229,195

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Microglia contribution to disease pathogenesis in C9orf72 ALS/FTD

Award Number: R01NS120331

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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