Wednesday, August 13, 2025 8/13/2025

Making a case for CASS4 in Alzheimer's disease

Award Number: R01AG087406
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Making a case for CASS4 in Alzheimer's disease - ABSTRACT Recent genome-wide association studies (GWAS) have consistently linked mutations in CASS4 (Cas Scaffold Protein Family Member 4) to an increased risk of developing late-onset Alzheimer’s disease. Yet, very little is currently known about the role of CASS4 in basic neurobiology or neurodegenerative disease pathogenesis. What little is known about CASS4 predominantly comes from studies exploring its biology in cell lines and cancer. These studies have helped to identify CASS4 as a member of the Crk-associated substrate (Cas) protein family. All members of the Cas family lack enzymatic activity and instead act as scaffold proteins. Cas proteins are best known for their central involvement in the regulation of focal adhesions, which are multiprotein signaling complexes that control cytoskeleton dynamics, adhesion, cell migration, and phagocytosis. To bridge the gap in our knowledge of the role of CASS4 in neurodegenerative disease progression, we recently generated both germline and conditional CASS4-deficient mice and have begun crossing these mice onto various mouse models of Alzheimer’s disease. In our preliminary studies, we have found that genetic ablation of CASS4 in the 5xFAD mouse model of Alzheimer’s disease leads to decreased recruitment of microglia to amyloid beta (Ab) plaques as well as defective compaction of Ab. Furthermore, we also observe markedly impaired cognitive flexibility and increased numbers of dystrophic neurites in 5xFAD mice that lack CASS4. On the molecular level, we also detect decreased focal adhesion signaling in CASS4-deficient macrophages. Based on our preliminary findings as well as the fact that Cass4 appears to be selectively expressed by microglia in the brain, we hypothesize that CASS4 is a central regulator of focal adhesion signaling that functions in microglia to limit Alzheimer’s-related disease progression. To test this working hypothesis, we will first explore how genetic ablation of CASS4 impacts neurodegenerative disease pathogenesis in mouse models of both Ab amyloidosis and tauopathy (Aim 1). Next, we will leverage our newly generated Cass4 conditional knockout mice to interrogate a microglia-specific role for CASS4 in controlling Alzheimer’s-related disease pathology and neuroinflammation (Aim 2). In our third Aim, we will explore how CASS4 affects focal adhesion signaling in microglia. Completion of the studies outlined in this application will break new ground in our understanding of the role of CASS4 in Alzheimer’s disease progression and microglial biology and will also help to establish new molecular players (i.e. CASS4) and pathways (i.e. focal adhesion signaling) that can be targeted to treat Alzheimer’s disease.


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 = $571,257 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	2	3/4/2025	NON-COMPETING CONTINUATION	$524,624
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	001	2	6/13/2025	NON-COMPETING CONTINUATION	$46,633
														Subtotal = $571,257

Issue Date FY: 2024 ( Subtotal = $550,614 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	1	6/11/2024	NEW	$550,614
														Subtotal = $550,614

Grand Total All Awards = $1,121,871

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Making a case for CASS4 in Alzheimer's disease

Award Number: R01AG087406

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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