The research of Chia-Chen Liu, Ph.D., is focused on understanding why the ε4 allele of the apolipoprotein E gene (APOE) represents a strong risk factor for Alzheimer's disease (AD), whereas APOE2 is protective. Specifically, Dr. Liu investigates the pathogenic pathways by which APOE and age-related risk factors impact the development of AD and cerebral amyloid angiopathy using various genetic disease models and human brain tissues.
Dr. Liu has developed innovative models allowing for inducible and cell-type-specific expression of human APOE isoforms. Using in vivo microdialysis, she also established techniques to measure the dynamic changes of Aβ and other disease-related proteins in the brains of living animals. Dr. Liu's research goal is to establish a foundation for developing mechanism-based therapeutic strategies and treatment for AD.
- APOE in brain function and Alzheimer's disease. Dr. Liu developed novel inducible disease models that allow expression of human APOE isoforms in a cell-type and time-dependent fashion. Her research interest is to access how APOE isoforms expressed by different cell types differentially affect critical brain functions, cognition and Aβ metabolism in AD.
- Neuronal heparan sulfate proteoglycan (HSPG) in amyloid pathogenesis and cerebrovascular diseases. Dr. Liu's studies provided in vivo evidence that HSPG inhibits brain Aβ clearance and promotes amyloid plaque deposition. Also, HSPG may influence the development of cerebral amyloid angiopathy in AD. These studies shed light on the mechanisms by which HSPG modulates brain A metabolism, and suggest that targeting Aβ-HSPG interaction might be a novel strategy to treat AD.
- Signaling pathways in Alzheimer's disease. Dr. Liu demonstrated that dysregulation of the low-density lipoprotein receptor-related protein 6 (LRP6)/Wnt signaling pathway impaired age-dependent synaptic function, and exacerbated amyloidogenesis. Her research also links apoE and LRP1, a major apoE receptor in the brain, to insulin signaling and glucose metabolism, which may provide novel insights into the association between insulin resistance and AD.
- Tauopathy seeding and propagation. Dr. Liu's studies will investigate how cell surface HSPG and APOE isoforms differentially regulate the development of tauopathies as well as the seeding and propagation of tau pathology.
- TREM2 in Alzheimer's disease. TREM2 is an innate immune receptor primarily expressed by microglia in the brain and is involved in inflammation and phagocytic clearance of Aβ and cellular debris. Dr. Liu's research aims at dissecting how TREM2-R47H, an AD-associated mutation, modulates microglial functions and amyloid development, which should provide mechanistic guidelines as to how microglia-mediated neuroinflammation can be targeted in AD therapy.
Significance to patient care
The ultimate goal of Dr. Liu's work is to contribute to the development of a treatment that successfully mitigates the risk of AD and the design of effective therapies for AD.
- Recipient, Alzheimer's Association Research Grant, 2017-2019
- Recipient, BrightFocus Research Grants Award, 2016-2018
- Recipient, American Heart Association fellowship, 2015-2017
- Recipient, Neurotherapeutics Discovery and Development Training Award, 2013-2015