Investigating the role of CSF production and circulation in aging and Alzheimer's disease

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Project Summary The choroid plexus (CP) and cerebral spinal fluid (CSF) system serve multiple active roles in regulating brain homeostasis and have been recently implicated in brain aging and cognitive function. Current work is focused on cataloging molecules in the CP-CSF system and determining the role of these molecules in both brain development as well as immune-brain interactions. CP atrophy has been observed in multiple CNS disorders, and a recent study shows that transplantation of young CSF into aged brains reverses age-related cognitive decline in rodents. Conditions that disrupt glymphatic circulation via CSF flow in the perivascular space have been linked to decrease amyloid and tau protein clearance from the brain. These observations in animal and human brain disorders indicate that the CP-CSF system plays a role in brain disease progression or exacerbation, especially during aging. However, despite its important roles, the CP-CSF system has largely remained an under-explored field in neuroscience due to limitations in the number of available tools to precisely modulate its functions. By using a novel transgenic mouse line that we recently discovered, our project will address the goals by (1) establishing a new tool to ablate the CP in mice during the aging process and (2) study the direct causal role of CSF production in maintaining brain health during aging and in Alzheimer's disease (AD) animal models. Our rigorous preliminary data indicate that (1) this line can induce exclusive apoptotic cell death only in CP epithelial cells, (2) the CP ablation results in partial to near-complete (50-90%) reduction in ventricular volume, depending on the dose and timing of agent administration and (3) ablation of CP and loss of CSF leads to increased accumulation of both extracellular Aβ plaques and phosphorylated intracellular protein. These preliminary data support a direct and causal role of CSF production in protein clearance in AD animal models. In this proposal, for the first time, we will investigate the dose-response effects of CP ablation on brain aging with a special focus on age-related neuroinflammation, neuronal survival, age-related neurogenesis decline and cognitive function. We will also assess the outcome of CP/CSF reduction in animal models of AD including both Aβ and tau AD models. We will focus on AD-related pathology such as extracellular Amyloid plaque formation, intracellular tau neurofibrillary tangles (NFTs), neurodegeneration, neuroinflammation and cognitive function. This project provides an essential platform for elucidating the role of CP-CSF in underlying brain aging and Alzheimer's related cognitive decline. By establishing a new tool to remove CP-CSF in mice at any desired timepoint (neonatal to adulthood), our project will make significant contributions and impact on promoting studies of the CP-CSF system in a wide range of topics in neuroscience and brain diseases.