Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of two proteins in fibrillar form: amyloid-β (Aβ) and tau. Despite decades of intensive research, we cannot yet pinpoint the exact cause of the disease or unequivocally determine the exact mechanism(s) underlying its progression. This confounds early diagnosis and treatment of the disease. Cerebrospinal fluid (CSF) biomarkers, which can reveal ongoing biochemical changes in the brain, can help monitor developing AD pathology prior to clinical diagnosis. Here we review preclinical and clinical investigations of commonly used biomarkers in animals and patients with AD, which can bridge translation from model systems into the clinic. The core AD biomarkers have been found to translate well across species, whereas biomarkers of neuroinflammation translate to a lesser extent. Nevertheless, there is no absolute equivalence between biomarkers in human AD patients and those examined in preclinical models in terms of revealing key pathological hallmarks of the disease. In this review, we provide an overview of current but also novel AD biomarkers and how they relate to key constituents of the pathological cascade, highlighting confounding factors and pitfalls in interpretation, and also provide recommendations for standardized procedures during sample collection to enhance the translational validity of preclinical AD models.
Projection neurons in the anteriolateral part of entorhinal cortex layer II are the predominant cortical site for hyperphosphorylation of tau and formation of neurofibrillary tangles in prodromal Alzheimer’s disease. A majority of layer II projection-neurons in anteriolateral entorhinal cortex are unique among cortical excitatory neurons by expressing the protein reelin. In prodromal Alzheimer’s disease, these reelin-expressing neurons are prone to accumulate intracellular amyloid-β, which is mimicked in a rat model that replicates the spatiotemporal cascade of the disease. Two important findings in relation to this are that reelin-signaling downregulates tau phosphorylation, and that oligomeric amyloid-β interferes with reelin-signaling. Taking advantage of this rat model, we used proximity ligation assay to assess whether reelin and intracellular amyloid-β directly interact during early, pre-plaque stages in anteriolateral entorhinal cortex layer II reelin-expressing neurons. We next made a viral vector delivering microRNA against reelin, along with a control vector, and infected reelin-expressing anteriolateral entorhinal -cortex layer II-neurons to test whether reelin-levels affect levels of intracellular amyloid-β and/or amyloid precursor protein. We analyzed 25.548 neurons from 24 animals, which results in three important findings. First, in reelin-expressing anteriolateral entorhinal cortex layer II neurons, reelin and intracellular amyloid-β engage in a direct protein-protein interaction. Second, injecting microRNA against reelin lowers reelin-levels in these neurons, amounting to an effect size of 1.3-4.5 (Bayesian estimation of Cohen’s d effect size, 95% credible interval). This causes a concomitant reduction of intracellular amyloid-β ranging across three levels of aggregation, including a reduction of Aβ42 monomers/dimers amounting to an effect size of 0.5-3.1, a reduction of Aβ prefibrils amounting to an effect size of 1.1-3.5, and a reduction of protofibrils amounting to an effect size of 0.05-2.1. Analyzing these data using Bayesian estimation of mutual information furthermore reveals that levels of amyloid-β are dependent on levels of reelin. Third, the reduction of intracellular amyloid-β occurs without any substantial associated changes in levels of amyloid precursor protein. We conclude that reelin and amyloid-β directly interact at the intracellular level in the uniquely reelin-expressing projection neurons in anteriolateral entorhinal cortex layer II, where levels of amyloid-β are dependent on levels of reelin. Since amyloid-β is known to impair reelin-signaling causing upregulated phosphorylation of tau, our findings are likely relevant to the vulnerability for neurofibrillary tangle-formation of this entorhinal neuronal population.
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 Alzheimer 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-β (iAβ). Biochemical pathways that involve reelin-signaling regulate levels of p-tau, and iAβ has been shown to impair such reelin-signaling. We therefore used the rat model and set out to assess whether accumulation of iAβ 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 iAβ42 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 iAβ 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 iAβ 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.
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 (Bjorkli, unpublished data).
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