Tapping into the aging brain:In vivomicrodialysis 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.

Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice

“…This is consistent with CSF t-tau concentrations increasing in the first few days following injury (i.e., probe implantation in our experiments), then reduction over time (Neselius et al, 2012). However, we have previously shown that long-term implantation of our microdialysis probes does not lead to observable neuroinflammation in 3xTg AD mice (Bjorkli et al, 2021). In addition, intracerebral microdialysis is an invasive technique, so it is currently only used in patients requiring neurocritical care, neurosurgery, or brain biopsy (Marklund et al, 2009).…”

“…Surgeries were based on previously established protocols (Bjorkli, 2021;Bjorkli et al, 2021), but in brief, implantation surgery was performed to insert microdialysis guide cannulas (CMA 7; CMA Microdialysis AB, Kista, Sweden) into the lateral ventricle of mice. Mice were anesthetized with isoflurane gas (4% induction and 1.5-3% maintenance; IsoFlo vet., Abbott Laboratories, Chicago, IL, United States) prior to being fixed in a stereotaxic frame (Kopf Instruments; Chicago, IL, United States).…”

“…Push-pull microdialysis was conducted as previously described (Bjorkli et al, 2021), but in brief a refrigerated fraction collector (CMA 470) was set to 6 °C for the storage of collected CSF in 300 µl low-retention polypropylene plastic vials (Harvard Apparatus, Cambridge, MA, United States). Fluorinated ethylene propylene (FEP) peristaltic tubing (CMA Microdialysis AB, Kista, Sweden) was placed inside each plastic vial for collection and connected to the cassette of the peristaltic roller pump (Reglo ICC Digital).…”

“…Here we have used the most complete transgenic mouse model for AD to date, the 3xTg AD mouse, which has been shown by us and others to develop agedependent amyloid plaque and NFT deposition (Oddo et al, 2003;Javonillo et al, 2022). We used an optimized protocol for intraventricular microdialysis (Bjorkli et al, 2021) to systemically target two promising therapeutic avenues, the Wnt and autophagic pathways, to attenuate Aβ and tau levels respectively, at the molecular and functional level. Many drugs that target these two pathways have displayed adverse side-effects in experimental models and patients, and we therefore opted to repurpose drugs that were already approved for clinical use.…”