Affiliations: [a]
Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| [b] Department of Neurology, St. Olav’s Hospital, Trondheim, Norway
| [c]
Center for Molecular Inflammation Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| [d]
Department of Clinical Neuroscience, Neuro, Head and Neck, Umeå University Hospital, Umeå, Sweden
| [e]
Department of Community Medicine and Rehabilitation, Neuro, Head and Neck, Umeå University Hospital, Umeå, Sweden
Correspondence:
[*]
Correspondence to: Christiana Bjorkli, Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology Edvard Griegs Gate 8, 7030 Trondheim, Norway. Tel.: +4741544063; E-mail: christiana.bjorkli@ntnu.no.
Abstract: Background:Preclinical 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 CSF monitoring. Objective: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. Here we draw upon patient-based findings to characterize CSF biomarkers in a commonly used preclinical mouse model for AD. Methods:Our modified push-pull microdialysis method was first validated ex vivo with human CSF samples, and then in vivo in an AD mouse model, permitting assessment of dynamic changes of CSF Aβ and tau and allowing for better translational understanding of CSF biomarkers. Results:We demonstrate that CSF biomarker changes in preclinical models capture what is observed in the brain; 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 parenchyma. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to CSF collection by lumbar puncture in patients. Conclusion:Our approach can further advance AD and other neurodegenerative 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.
Keywords: Amyloid-β
, animal use alternatives, biomarkers, cerebrospinal fluid, neurodegenerative disease, protein aggregation, tau protein
