Defining the Role of Varicose Projection Astrocytes in Alzheimer's Disease Pathology

About This Grant

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that remains without effective treatment. Mounting evidence suggests that neuroinflammation plays a critical role in AD progression, yet the contribution of astrocytes—a major glial cell type involved in brain homeostasis—remains poorly defined. Recent discoveries from our lab have identified varicose projection (VP) astrocytes as a novel, reactive astrocyte phenotype associated with neuroinflammatory conditions, including AD. Unlike traditional astrocytes, VP astrocytes display distinct morphological features (long processes with evenly spaced varicosities), are enriched in the cortex and white matter of AD brains, and can be experimentally induced in vitro by pro-inflammatory cytokines. Importantly, the VP astrocyte phenotype is reversible upon cytokine withdrawal, highlighting its potential as a targetable cellular response in AD. This AREA R15 project aims to elucidate the role of VP astrocytes in AD pathology using human-induced pluripotent stem cell (hiPSC)-based models and human postmortem brains. The project will engage undergraduate researchers at Towson University in Dr. Falcone’s lab and within a novel neuroscience Course- Based Undergraduate Research Experience (CURE). Here, we propose to investigate the role of VP astrocytes in AD pathology through two aims: (Aim 1) Define the molecular signature of VP astrocytes in AD-associated neuroinflammation using Patch-seq transcriptomic profiling and validation in human postmortem brain tissue; (Aim 2) Assess the functional impact of VP astrocytes on neuronal degeneration using hiPSC-derived neuron-astrocyte co-cultures, testing cytokine withdrawal and pharmacological inhibition of key inflammatory pathways. By integrating cellular, molecular and anatomical approaches in human-based models, this project will reveal the mechanistic contribution of VP astrocytes to AD, laying the groundwork for novel therapeutic strategies while training the next generation of biomedical scientists.