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Studying roles of CASP8 SVA GGGAGA repeat expansions in Alzheimer's disease

Award Number: R01AG093746
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Studying roles of CASP8 SVA GGGAGA repeat expansions in Alzheimer's disease - Project summary Alzheimer’s disease (AD), the most common form of dementia, is characterized by cognitive decline and impairment of behavioral and functional abilities. Approximate 6.7 million people in the United States are affected by AD and this number is anticipated to triple by 2060. While mutations in amyloid precursor protein (APP) and presenillin (PSEN1 and PSEN2) are known to cause familial early onset AD and the APOE4 variant is a common disease risk factor, the genetic contributions to the majority of late onset AD cases are not clear. While the accumulation of Aβ plaques and hyperphosphorylated tau (pTau) are the hallmark features of AD, it is not clear if targeting Aβ plaques or pTau is an effective treatment strategy for sporadic AD. Our recent findings strongly support the contribution of microsatellite repeat expansions in AD. Using antibodies targeting polymeric proteins reported in known repeat expansion disorders, we show poly-glycine-arginine (polyGR+) aggregates are frequently found in AD brains with unknown genetic etiologies. Using a repeat expansion pulldown tool, we identified a novel polyGR-encoding GGGAGA repeat expansion in CASP8 (CASP8-GGGAGAEXP). The CASP8- GGGAGAEXP produces polyGR-containing proteins in CASP8-GGGAGAEXP(+) AD brains and in transfected cells. A rare, specific variant of this expansion, CASP8ADR1 containing stretches of (GGGAGA)4CG motifs is associated with increased AD risk in three independent cohorts (odds ratio = 2.2, p<0.0001). We also show CASP8ADR1 produces higher levels of rGGGAGAEXP RNA inclusion and polyGR aggregates, and is more toxic than the common CASP8-GGGAGAEXP variant in cells. Our finding is exciting because it connects AD to a large family of >70 rare neurological disorders caused by repeat expansion mutations including C9orf72 frontotemporal dementia (FTD) (C9-FTD). Molecular mechanisms of these diseases involve protein loss- or gain- of-function (GOF), RNA GOF, and the toxicity of polymeric proteins produced by repeat-associated non-AUG (RAN) translation. PolyGR proteins have been shown to be highly toxic in C9 FTD models. In AD autopsy brains, polyGR+ aggregates are increased with AD pathological hallmarks (e.g. increased pTau in the hippocampus and increased Aβ plaque and pTau deposition). Interestingly, polyGR+ aggregate levels are increased in AD cases that experience brain injuries and high blood pressure that have been shown to induce oxidative stress. We hypothesize that CASP8ADR1 contributes to AD by producing toxic RAN proteins and oxidative stress increases AD risk in CASP8ADR1 carriers by increasing the accumulation of RAN protein aggregates. We will test this hypothesis in three specific aims: Aim 1) To test the hypothesis that expansion RNAs and polyGR-containing proteins expressed from CASP8ADR1 accumulate in regions with AD pathology in CASP8ADR1(+) AD autopsy brains; Aim 2) To test the hypothesis that CASP8ADR1 alleles produce repeat expansion products that are associated with molecular hallmarks of AD in patient derived organoids; and Aim 3) To test the hypothesis that removing or blocking expression of the CASP8ADR1 will mitigate disease phenotypes in patient derived models.


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 = $507,371 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	2	3/26/2026	NON-COMPETING CONTINUATION	$507,371
														Subtotal = $507,371

Issue Date FY: 2025 ( Subtotal = $507,371 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	1	5/28/2025	NEW	$507,371
														Subtotal = $507,371

Grand Total All Awards = $1,014,742

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Studying roles of CASP8 SVA GGGAGA repeat expansions in Alzheimer's disease

Award Number: R01AG093746

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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