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APC Signaling in Neurodegenerative Diseases Image Long Description

Overview

Single-Cell RNA sequencing reveals changes in cell population in Alzheimer’s disease (AD) model 5xFAD (5x Familial AD mutation) versus wild type mice. Uniform Manifold Approximation and Projection (UMAP) dimensional plot of the primary integrated dataset split by sample; list of unsupervised clusters colored by cell-type annotated. Differential expression levels of Ctsb in various cell-type of 5xFAD versus wild type mice. Epilepsy is a neurological disorder and is characterized by recurrent seizures. A few of the mechanisms of development involved brain blood barrier disruption, neuroinflammation, and microglia activation. APC, well known for its anticoagulant properties, has neuroprotective effects that could protect the brain blood barrier, activate anti-inflammatory and anti-apoptosis mechanisms, and lead to neurogenesis, all of which could help prevent or protect against epilepsy. Thus, APC neuroprotection in epilepsy pathophysiology could inhibit blood brain barrier leakage, apoptosis, and inflammatory mechanism in disease development.

Presentation

Top left panel: UMAP dimensional plot of the cell type clusters of mouse brain. X-axis is labeled UMAP_1 with a value range of -10 to 15. Y-axis is labeled UMAP_2 with a value range of -10 to 10. Plot values from top to bottom have the labels Endothelial (gold), Oligodendrocyte (blue), OPC (magenta), Astrocyte (red), Neuron (turquoise) and Microglia (green). Each dimensional plot is the same color as the label. From left to right, the labels appear in this order: Microglia, Oligodendrocyte, Endothelial, Astrocyte, Neuron and OPC. In terms of area, the Oligodendrocyte dimensional plot has the most distribution while Neuron has the least.

Top right panel: Violin plot of the relative expression levels of Ctsb gene in cell types of mouse brain. The X-axis has the labels Astrocyte in red, Endothelial in gold, Microglia in green, Neuron in turquoise, Oligodendrocyte in blue and OPC in magenta. The violin plot above each label is the same color. The Y-axis is labeled Expression Level with a value range of 0 to 4. The height of the violin plots from tallest to shortest are Neuron, Microglia, Endothelial, OPC, Oligodendrocyte and Astrocyte. The width of the violin plot from widest to narrowest are Neuron, Microglia, Astrocyte, OPC, Oligodendrocyte and Endothelial.

Note that the figures for the graphs in the top panels were generated from Single-Cell RNA Seq (Bioinformatic approach). Thus, it cannot give numeric values.

Bottom panel: Illustration of a synapse (light blue) releasing glutamate.

• Presynaptic terminal has these labels and depictions:

  • Glutamate (blue balls within a circle)

  • Glutamate release (blue balls coming out of a 3/4 circle)

    • Blue arrow points from the circle to the 3/4 circle

  • C1q (dark yellow object with one point on one end and four tendrils on the other end)

  • C1q relocalization (dark yellow arrow pointing down to indicate movement)

  • Another C1q rotated in the opposite direction)

  • Black arrow pointing down to an item labeled C3 (a capsule shape on the barrier of the terminal with a turquoise semicircle on the end outside of the terminal)

• Postsynaptic terminal has these labels and depictions:

  • NMDAR (narrow blue butterfly shape)

  • AMPAR (narrow dark yellow butterfly shape)

  • Another C1q with a black arrow pointing to a C3

  • Three up arrow (one black, two gray) with the label Ca²⁺ Excitation.

  • Mitochondria (beige) with four green circles to the top left labeled Cytochrome C.

• To the left of the synapse is an astrocytic endfoot (pink) with these labels and depictions:

  • Albumin (yellow circle above four brown hook-shaped objects) extending from the center of the endfoot

  • STAT3 (orange rounded rectangle above a purple helix) within a light pink circle

  • GLT1 (thick pink opening) on the wide end of the endfoot

  • A bent black arrow points from the STAT3 to the GLT1

• To the right of the synapse is a microglial process (turquoise) with a turquoise semicircle to the left of the widest part labeled CR3/CR4.

• Top left inset: Cutaway view of blood-brain barrier with the labels Albumin, IgG, erythrocytes, ions (hilly red and orange surface with purple spikes on top and pink foundation with one red circle and four yellow circles), and five circles labeled K float from the bottom (one purple, four gray)

• Negative space:

  • Three oblong, curved red objects labeled APC. Top left one is labeled Blood-brain barrier leakage, bottom left one is labeled Apoptosis, and bottom right one is labeled Inflammation

  • Three purple balls to the right of the post-synaptic terminal is labeled Interleukine/Cytokine

  • An additional NMDAR and AMPAR lie on the barrier of the pre-synaptic terminal

  • Glutamate enters through the GLT1 on the Astrocytic endfoot with a left blue arrow indicating motion

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