Caghan Kizil, PhD, MSc

Resilience Biology and Regeneration in Alzheimer’s Disease

Our laboratory, Kizil Lab, investigates why the brain becomes vulnerable in Alzheimer’s disease and how its natural resilience and repair mechanisms can be restored. Using functional genomics tools and the zebrafish brain - a uniquely regenerative and genetically tractable in vivo system, we investigate mechanisms of resilience against Alzheimer’s disease. We integrate these findings with evidence from human postmortem tissue, clinical genetic studies, single-cell multi-omics, advanced 3D complex human in vitro culture systems, and mouse models to identify molecular principles that govern vulnerability and protection. Our broader mission is to define the biological programs that preserve brain function and translate them into disease-modifying therapeutic strategies.

How the brain repairs itself

We study how neural stem cells lose their ability to proliferate and generate new neurons in Alzheimer’s disease, and why zebrafish retain this remarkable regenerative capacity. Our work has shown that the zebrafish brain activates a coordinated repair program involving immune-derived cues, neurotransmitter signaling, and microenvironmental shifts that restore stem-cell plasticity. These mechanisms reveal how damaged brains can be stimulated to produce new neurons and inform how such pathways might be re-engaged in mammalian systems.

Protecting the blood-brain barrier

Our research has demonstrated how the blood–brain barrier deteriorates in the context of genetic risk for Alzheimer’s disease and how specific cellular interactions can restore its function. A major discovery from our group identifies fibronectin as a key molecular driver of vascular pathology, particularly in individuals carrying risk variants such as APOE4. Elevated fibronectin disrupts barrier structure and promotes inflammation, while reduced fibronectin activity is linked to protection and preserved brain integrity. Through single-cell analyses, human stem-cell models, and zebrafish, we investigate how vascular cells and astrocytes communicate during disease and how these pathways can be therapeutically targeted.

What makes a brain resilient?

We integrate large-scale human genetic studies with cross-species functional modeling to uncover why some individuals develop Alzheimer’s while others with comparable risk remain cognitively resilient. By rapidly testing the biological consequences of human genetic variants in zebrafish, we identify conserved pathways that drive either vulnerability or protection. This approach provides a powerful framework for defining molecular signatures of resilience.

Harnessing resilience for new therapies

A central aim of the lab is to convert fundamental discoveries into therapeutic innovation. We use human 3D brain and vascular models, high-throughput zebrafish platforms, and structure-guided pharmacology to identify compounds that enhance regeneration, strengthen the blood–brain barrier, or modulate the extracellular environment. Our translational efforts have catalyzed entrepreneurial initiatives and are driving the development of resilience-based therapeutics inspired by the protective biology of zebrafish and human genetic variants.