# Making a case for CASS4 in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $550,614

## Abstract

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.

## Key facts

- **NIH application ID:** 10885349
- **Project number:** 1R01AG087406-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** John R Lukens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,614
- **Award type:** 1
- **Project period:** 2024-06-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885349

## Citation

> US National Institutes of Health, RePORTER application 10885349, Making a case for CASS4 in Alzheimer's disease (1R01AG087406-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10885349. Licensed CC0.

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