Biology subjects

Bjorkli, C.

Publications and source records attributed to Bjorkli, C..

3 recordsLinked to original sources

bioRxiv2022

Lowering levels of reelin in entorhinal cortex layer II-neurons results in lowered levels of intracellular amyloid-β.

Projection neurons in the anterolateral part of entorhinal cortex layer II (alEC LII) are the predominant cortical site for hyperphosphorylation of tau (p-tau) and formation of neurofibrillary tangles (NFTs) in brains of subjects with early-stage Alzheimers Disease (AD). A majority of alEC LII-neurons are unique among cortical excitatory neurons by expressing the protein reelin (Re+). In AD patients, and a rat model for AD overexpression mutated human APP, these Re+ excitatory projection-neurons are prone to accumulate intracellular amyloid-{beta} (iA{beta}). Biochemical pathways that involve reelin-signaling regulate levels of p-tau, and iA{beta} has been shown to impair such reelin-signaling. We therefore used the rat model and set out to assess whether accumulation of iA{beta} in Re+ alEC LII projection neurons relates to the fact that these neurons express reelin. Here we show that in Re+ alEC LII-neurons, reelin and iA{beta}42 engage in a direct protein-protein interaction, and that microRNA-mediated lowering of reelin-levels in these neurons leads to a concomitant reduction of non-fibrillar iA{beta} ranging across three levels of aggregation. Our experiments are carried out several months before plaque pathology emerges in the rat model, and the reduction of iA{beta} occurs without any substantial associated changes in human APP-levels. We propose a model positioning reelin in a sequence of changes in functional pathways in Re+ alEC LII-neurons, explaining the region and neuron-specific initiation of AD pathology. SignificanceAnterolateral entorhinal cortex layer II (EC LII) neurons are the predominant cortical site for hyperphosphorylation of tau (p-tau) and formation of neurofibrillary tangles (NFTs) in brains of subjects with early-stage Alzheimers disease (AD). The same neurons are prone to very early accumulation of non-fibrillary forms of amyloid-{beta} in the context of AD, and are unique among cortical excitatory neurons by expressing the protein reelin. We show that in such alEC LII-neurons, reelin and iA{beta}42 engage in a direct protein-protein interaction, and that selectively lowering levels of reelin leads to a concomitant reduction of non-fibrillar A{beta}. We propose a model positioning reelin in a sequence of changes in functional pathways in reelin-expressing EC LII neurons, explaining the region and neuron specific initiation of AD.

pathology↗

bioRxiv2022

Using intracerebral microdialysis to probe the efficacy of repurposed drugs in Alzheimer's disease pathology

All disease-targeting drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimers disease patients. Even the recently approved drug Aducanumab, has proven effective in removing amyloid-{beta}, but does not reduce cognitive decline. This emphasizes the urgent need for novel therapeutic approaches that could reduce several AD neuropathologies simultaneously, eventually leading to improved cognitive performance. To validate whether our mouse model replicates AD neuropathology as observed in patients, we characterized the 3xTg AD mouse model to avoid premature translation of successful results. In this study we have repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting the Wnt signaling and endosomal-lysosomal pathway respectively, to test their potential to attenuate AD pathology. Using intracerebral microdialysis, we simultaneously infused these disease-targeting drugs between 1-2 weeks, separately and also in combination, while collecting cerebrospinal fluid. We found that Fasudil reduces intracellular amyloid-{beta} in young, and amyloid plaques in old animals, and overall cerebrospinal fluid amyloid-{beta}. Lonafarnib reduces tau neuropathology and cerebrospinal fluid tau biomarkers in young and old animals. Co-infusion of both drugs was more effective in reducing intracellular amyloid-{beta} than either drug alone, and appeared to improve contextual memory performance. However, an unexpected finding was that Lonafarnib treatment increased amyloid plaque size, suggesting that activating the endosomal-lysosomal system may inadvertently increase amyloid-{beta} pathology if administered too late in the AD continuum. Taken together, these findings lend support to the application of repurposed drugs to attenuate AD neuropathology at various therapeutic time windows. One Sentence SummaryHere we circumvented the blood-brain barrier for drug delivery aimed at attenuating AD neuropathology.

neuroscience↗

bioRxiv2021

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

Preclinical models of Alzheimers disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-{beta} (A{beta}) 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 A{beta} and tau in CSF and allows for better translational understanding of CSF biomarkers. Specifically, we demonstrate that CSF concentrations of A{beta} and tau along disease progression in transgenic mice mirror what is observed in patients, with a decrease in CSF A{beta} 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 A{beta} 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.

neuroscience↗