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Mechanism of innate immune activation in a Drosophila model of Alzheimer's disease related dementia

Award Number: R01AG075100
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanism of innate immune activation in a Drosophila model of Alzheimer's disease related dementia - ABSTRACT: Lewy body dementia is an Alzheimer’s disease–related dementia that affects more than one million Americans. The strongest risk factor for this devastating neurodegenerative disease is mutation of the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA mutations can impair the ability of GCase to break down its substrate, the glycosphingolipid glucosylceramide (GlcCer), but it is not clear how defects in GlcCer breakdown increase the risk of Alzheimer’s disease–related dementias. To study this problem, we created a fly lacking the Drosophila ortholog of GBA, Gba1b, as a model of GCase deficiency. Our Gba1b mutant shows accumulation of GlcCer and recapitulates features of Alzheimer’s disease–related dementias including neurodegeneration, brain protein aggregates, and age-related cognitive decline. We now propose to use the Gba1b mutant to test a novel model of neurodegeneration associated with GCase deficiency, in which GlcCer accumulation leads to neuroinflammation via changes in extracellular vesicles (EVs). In earlier work, we found that Gba1b mutants had increased abundance and turnover of EV proteins, and that genetically suppressing neuronal EV production ameliorated mutant phenotypes. More recently, RNA-Seq experiments revealed that Gba1b mutants had marked innate immune activation. A followup RNAi screen of major innate immune pathways found that neuronal knockdown of two p38 MAPK pathway components, the transcription factor Atf-2 and its upstream kinase licorne, also suppressed Gba1b mutant phenotypes. Based on these and other findings, we hypothesize that immune-mediated neurodegeneration in Gba1b mutants is a process driven by excess GlcCer in two separate roles. Specifically, we hypothesize that excess GlcCer in neurons triggers ligand-independent receptor tyrosine kinase activity and p38 MAPK signaling, stimulating EV release; GlcCer in the released EVs then causes glia to secrete immune effector proteins, leading to protein aggregation and neurodegeneration. We propose three aims to address these hypotheses. The first will delineate the intraneuronal signaling pathway that leads to abnormal EV release; the second will investigate the nature of the EV alterations; the third will determine how those EVs trigger immune effector secretion from glia. Given the abundant evidence for neuroinflammation in Alzheimer’s disease and related dementias, we anticipate that our work will have broad medical significance.


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 = $388,750 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	5	1/15/2026	NON-COMPETING CONTINUATION	$349,875
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	001	5	2/23/2026	NON-COMPETING CONTINUATION	$38,875
														Subtotal = $388,750

Issue Date FY: 2025 ( Subtotal = $380,975 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	4	1/24/2025	NON-COMPETING CONTINUATION	$349,875
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	001	4	8/11/2025	NON-COMPETING CONTINUATION	$31,100
														Subtotal = $380,975

Issue Date FY: 2024 ( Subtotal = $388,750 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	001	3	6/25/2024	NON-COMPETING CONTINUATION	$38,875
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	3	2/1/2024	NON-COMPETING CONTINUATION	$349,875
														Subtotal = $388,750

Issue Date FY: 2023 ( Subtotal = $388,750 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	2	1/27/2023	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2022 ( Subtotal = $388,750 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	1	1/24/2022	NEW	$388,750
														Subtotal = $388,750

Grand Total All Awards = $1,935,975

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Mechanism of innate immune activation in a Drosophila model of Alzheimer's disease related dementia

Award Number: R01AG075100

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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