Tapping into the aging brain: In vivo microdialysis reveals mirroring pathology between preclinical models and patients with Alzheimer’s disease

Abstract

SUMMARYPreclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal monitoring of CSF akin to methods employed in AD patients. An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Our novel push-pull microdialysis method in AD mice permits in vivo longitudinal monitoring of dynamic changes of Aβ and tau in CSF and allows for better translational understanding of CSF biomarkers. Specifically, we demonstrate that CSF concentrations of Aβ and tau along disease progression in transgenic mice mirror what is observed in patients, with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to lumbar puncture CSF collection in patients. We furthermore provide specific recommendations for optimal application of our novel microdialysis method, such as achieving optimal recovery of analytes, which depends heavily on the flow rate of perfusion, probe properties and perfusate composition. Our approach can further advance AD research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal, and can additionally be used to administer pharmaceutical compounds and assess their efficacy in treating AD.