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'Defining the Mechanisms Underlying the Protective Effects of the Reelin-COLBOS Variant in Alzheimer's Disease (AD)

Award Number: R21AG101719
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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'Defining the Mechanisms Underlying the Protective Effects of the Reelin-COLBOS Variant in Alzheimer's Disease (AD) - PROJECT SUMMARY ABSTRACT The majority of genome-wide association studies (GWAS) in Alzheimer’s disease (AD) have focused on identifying genetic variants that increase disease risk, leading to therapeutic strategies aimed at mitigating these effects. In contrast, the investigation of protective genetic variants offers a complementary approach to uncover novel therapeutic targets for AD prevention. To this end, a rare Reelin variant (H3447R, termed RELN-COLBOS) was identified in a PSEN1 mutation carrier and is associated with mitigated neurodegeneration and cognitive decline. Understanding the protective mechanisms conferred by RELN-COLBOS could reveal novel targets for Alzheimer's disease prevention and therapy. In this proposal, we will leverage our expertise in stem cell bioengineering, genome editing, and neurodegenerative disease modeling to elucidate the neuroprotective mechanisms of the RELN-COLBOS variant. In Aim 1, we will use our optimized genome editing approaches to introduce the RELN-COLBOS variant into isogenic human induced pluripotent stem cells (hiPSCs) derived from healthy non-demented control (NDC) and AD patient lines. In Aim 2, we will differentiate these lines into neurons, astrocytes, and microglia and conduct biochemical, molecular, and transcriptomic analyses to assess the impact of RELN-COLBOS on AD-related phenotypes. Specifically, we will evaluate whether this variant modulates (i) amyloid precursor protein (APP) processing and Aβ secretion, and (ii) tau phosphorylation and aggregation. Additionally, transcriptomic profiling will be used to determine whether RELN-COLBOS drives broader neuroprotective transcriptional changes in signaling pathways and gene regulatory networks. Finally, by comparing RELN-COLBOS-expressing lines to RELN knockout hiPSCs, we will determine whether the variant functions through a gain- or loss-of-function mechanism. Overall, a better understanding of potential genetic factors, such as the RELN-COLBOS variant that enhance neuroprotection against AD will provide new avenues for therapeutic interventions.


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 = $431,750 )
2026	2026	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Aging Research	000	1	8/28/2026	NEW	$431,750
														Subtotal = $431,750

Grand Total All Awards = $431,750

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'Defining the Mechanisms Underlying the Protective Effects of the Reelin-COLBOS Variant in Alzheimer's Disease (AD)

Award Number: R21AG101719

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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