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Complement signaling in Alzheimer's Disease pathogenesis

Award Number: R03AG098212
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Complement signaling in Alzheimer's Disease pathogenesis - Synaptic pathology is the hallmark of neurodegeneration that is most highly correlated with memory impairment in Alzheimer's disease (AD). Complement is a humoral innate immune system that plays an important role in synaptic plasticity. Although a number of studies, over the last four decades, have implicated complement dysregulation in AD, the brain cell-specific role of complement signaling in AD pathophysiology is still not known. The complement component 3 (C3) is the converging point of all complement activation pathways.C3 signals through its receptor, C3a receptor 1 (C3ar1). Studies complement using microglia till date have focused on the role of on brain plasticity with a cellular f ocus on microglia in AD, and these studies were conducted C3ar1 global knockout mice. However, it is not known whether C3ar1 signaling through neurons and are essential for memory impairment and synaptic loss during amyloidosis, a significant knowledge gap which this proposal will be seeking to address. Our preliminary data show that neuron-specific deletion of C3ar1 in mice results in deficits in recognition memory suggesting an important role of neuronal C3ar1 in normal CNS function. However, we did not find any significant changes in memory in mice with C3ar1 deleted in microglia. On the other hand, ablation of C3ar1 in microglia attenuates chronic stress-induced neuroinflammation and synaptic loss in mice. While chronic stress is known to enhance the formation of Aβ, it is important to investigate whether neuronal and microglial C3ar1 play critical roles in memory and synapse loss in a mouse model of amyloidosis. To address this question, we propose to use 5XFAD mice, a well- studied Aβ model, in which amyloid fibrils are known to promote complement-dependent synapse elimination. Our specific hypothesis is that ablation of microglial, but not neuronal C3ar1 attenuates memory impairment and synaptic loss associated with Aβ plaques. Using mice lacking C3ar1 selectively in microglia or excitatory neurons of the 5XFAD mice, we will determine the cell specific contribution of the C3ar1 on cognitive function, synapse loss and neuroinflammation in 5XFAD mice. The findings from the study may provide a better understanding on the role of brain complement signaling in AD pathogenesis. In addition, such data can be useful while designing future target-specific anti-complement therapies for AD.


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 = $312,000 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	8/18/2026	NEW	$312,000
														Subtotal = $312,000

Grand Total All Awards = $312,000

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Complement signaling in Alzheimer's Disease pathogenesis

Award Number: R03AG098212

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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