Fig 1.
Quantification of reelin levels across cortical regions in wild type rats.
Ten animals from three age groups were used in the study (3 months: 4; 12 months: 3; 18 months: 3). Brains were processed as detailed in reference [8]. Briefly, we quantified reelin-levels by way of densitometric measurement of cell profiles (primary antibody = Mouse anti-reelin (G10), Merk, Cat# MAB5364; RRID: AB_2179313; secondary antibody = Alexa 635 Goat anti-mouse (ThermoFisher, Cat# A-31574) in QuPath (Version 0.5.0). For each animal, we randomly selected three sections between Bregma level -5.64 and -6.48 on which the quantifications were done. On these sections, we selected our regions of interest (ROI) to cover the full extent of the cell layers. We adjusted the settings to include the maximum number of detections, such that for each ROI, virtually all available space was separated into unique cell profiles. Then, all cell profiles were assayed. For each section, we measured the signal in the underlying cortical white matter and used this for background subtraction. In rare instances, cell profiles where detected at borders where the tissue was very thin due to tearing. Occasionally, following background subtraction, these instances gave rise to negative reelin signals (0.02% of the total cell profiles). These cases were deleted from the dataset. In all boxplots, the whiskers cover the whole range of data. LECLII = anteriolateral entorhinal cortex layer II (marked in blue), V1 = primary visual cortex, RSCtx = retrosplenial cortex, HP = hippocampus, LECLIII-VI = anteriolateral entorhinal cortex layers III-VI.
Table 1.
Parameter values used to describe LR and Re+alECLII neurons.
Note that the αinfection value for Re+alECLII neurons was found by demanding that the maximum [Aβ] level during infection should be about the same as for LR neurons. See main text for further explanation.
Fig 2.
Immune response in LR neurons.
The four panels show how the levels of free Aβ, free reelin, Aβreelin and the proportion of phosphorylated GSK3β relative to the total amount of GSK3β (Gtot) develop during an infection event lasting 120 hours (from t = 50 to t = 170). The blue, orange, and green colors describe the pre-infection, infection, and post-infection phases, respectively. See the main text for further explanation.
Fig 3.
Immune response in Re+alECLII neurons.
The four panels show how the levels of free Aβ, free reelin, Aβreelin and the proportion of phosphorylated GSK3β relative to the total amount of GSK3β (Gtot) develop during an infection event lasting 120 hours (from t = 50 to t = 170). See the main text for further explanation.
Fig 4.
Immune response in Re+alECLII neurons with the COLBOS reelin mutation.
The parameter values are identical with those of the ApoEϵ3/ϵ3 genotype, except that γ=0.0000001, i.e., we assume that the reelin mutation is genetically dominant and causes a dramatic reduction in affinity between reelin and Aβ. The four panels show how the levels of free Aβ, free reelin, Aβreelin and the proportion of phosphorylated GSK3β develop during an infection event lasting 120 hours (from t = 50 to t = 170). See the main text for further explanation.
Fig 5.
Immune response in ApoEϵ4/ϵ4 Re+alECLII neurons.
The parameter values for the ApoEϵ4/ϵ4 genotype are identical with those of the ApoEϵ3/ϵ3 genotype, except that ρ=0.2. The four panels show how the levels of free Aβ, free reelin, Aβreelin and the proportion of phosphorylated GSK3β develop during an infection event lasting 120 hours (from t = 50 to t = 170). See the main text for further explanation.
Fig 6.
Recapitulating the effects of miRNA intervention in Re+alECLII neurons of McGill-R-Thy1-APP rats.
Panels A and B are identical with panels 1 and 4 in Fig 4A in reference [8]. The black vertical lines denote the mean values of the distributions in the experimental group of neurons. The green vertical lines denote the mean values of the distributions in the control group of neurons. The ratios of the mean values of the experimental group to the mean values of the control group are 0.26 and 0.69, respectively. C. Predicted steady state total number of reelin in experimental neurons as a function of the fold change of αbaseline in transgenic rats (Tg) compared to wild type and the fractional decrease of τ relative to wild type. Only a small subset of the fold change values and the fractional change values used in the numerical study is shown. The vertical dashed line denotes the predicted fractional reduction in the reelin production rate relative to wild type (0.14) that best fits the data. The horizontal dashed line denotes the total copy number of reelin when the fold change is 2.57. D. Predicted steady state total copy number of Aβ42 in experimental neurons as a function of the fold change of αbaseline relative to wild type and the fractional decrease of τ relative to wild type. The horizontal dashed line denotes the total copy number of Aβ42 when the fold change is 2.57.