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. 2009 Jul;175(1):271-82.
doi: 10.2353/ajpath.2009.090044.

Independent effects of intra- and extracellular Abeta on learning-related gene expression

Bettina M Wegenast-Braun  1 , Ana Fulgencio Maisch, Daniel Eicke, Rebecca Radde, Martin C Herzig, Matthias Staufenbiel, Mathias Jucker, Michael E Calhoun
Affiliations

Independent effects of intra- and extracellular Abeta on learning-related gene expression

Bettina M Wegenast-Braun et al. Am J Pathol. 2009 Jul.

Abstract

Alzheimer's disease is characterized by numerous pathological abnormalities, including amyloid beta (Abeta) deposition in the brain parenchyma and vasculature. In addition, intracellular Abeta accumulation may affect neuronal viability and function. In this study, we evaluated the effects of different forms of Abeta on cognitive decline by analyzing the behavioral induction of the learning-related gene Arc/Arg3.1 in three different transgenic mouse models of cerebral amyloidosis (APPPS1, APPDutch, and APP23). Following a controlled spatial exploration paradigm, reductions in both the number of Arc-activated neurons and the levels of Arc mRNA were seen in the neocortices of depositing mice from all transgenic lines (deficits ranging from 14 to 26%), indicating an impairment in neuronal encoding and network activation. Young APPDutch and APP23 mice exhibited intracellular, granular Abeta staining that was most prominent in the large pyramidal cells of cortical layer V; these animals also had reductions in levels of Arc. In the dentate gyrus, striking reductions (up to 58% in aged APPPS1 mice) in the number of Arc-activated cells were found. Single-cell analyses revealed both the proximity to fibrillar amyloid in aged mice, and the transient presence of intracellular granular Abeta in young mice, as independent factors that contribute to reduced Arc levels. These results provide evidence that two independent Abeta pathologies converge in their impact on cognitive function in Alzheimer's disease.

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Figures

Figure 1
Figure 1
Amyloid deposition in mouse models with distinct aspects of Alzheimer’s disease pathology. A: APPPS1 mice exhibit almost exclusively parenchymal amyloid, with plaques distributed throughout the neocortex. Shown is a 9-month-old mouse with a neocortical plaque load of 9.6%. B: APPDutch mice exhibit almost exclusively vascular amyloid, with pathology varying from smooth immunoreactivity in the vessel wall (arrow) to fibrils radiating from the vessel into the neuropil (arrowheads). An example of a more severely affected 29-month-old mouse is shown. C: APP23 mice develop both parenchymal and vascular pathologies. A 25-month-old mouse with neocortical plaque load of 8.5% is depicted. Scale bar: 200 μm (A–C).
Figure 2
Figure 2
Intracellular granular Aβ is present predominantly in cortical layer V (shown here in a young APP23 mouse) and is localized subcellularly at locations distinct from APP. A: Layer distribution of Aβ and Arc mRNA expression in the neocortex (S1 somatosensory cortex shown). The left-most panel illustrates normal Arc mRNA expression in a nontransgenic animal. Note the Arc expression in the non-transgenic cortical layer V neurons. Intracellular granular Aβ staining is shown in a young APP23 mouse at the age of 3.5 months. With increasing amyloid deposition, a decline in intracellular granular Aβ was apparent and virtually zero positive neurons remained in an aged (25-month-old) depositing APP23 mouse. (red: Arc mRNA; green: Aβ; blue: DRAQ5). B: The intracellular granules are distinct in size, subcellular distribution, and staining intensity (NT12; green) when compared with the diffuse cytoplasmic labeling observed with staining for APP (22C11; red). An overlay with cell nuclei (DRAQ5; blue) is also shown. Scale bars: 50 μm (A); 10 μm (B).
Figure 3
Figure 3
Reduced Arc mRNA expression in mouse models of cerebral amyloidosis. A decrease in the number of Arc mRNA-expressing neurons in the neocortex and dentate gyrus following exploratory behavior was observed for parenchymal and vascular depositing mice as well as for young animals before amyloid deposition. A: Prominent Arc mRNA expression (red) is evident throughout all neocortical layers in a ntg control mouse (top-left; example shown at 29 months of age–see Materials and Methods for matched ages in all groups). In comparison, reduced Arc mRNA induction is evident within the neocortex of Aβ depositing mice (APPPS1 [9 mo], APPDutch [29 mo], and APP23 [25 mo]); (red: Arc mRNA; green: Aβ; blue: cell nuclei [DAPI]). Scale bar = 200 μm. The inlay shows Arc-positive neurons with cytoplasmic Arc mRNA and/or intranuclear foci, referring to the different activation time points of the cells. Scale bar = 20 μm. B: A small percentage of dentate gyrus granule cells express high levels of Arc mRNA in a ntg control mouse (top-left; 29 months old), whereas a reduction of Arc mRNA-expressing dentate gyrus granule cells is evident for aged APPPS1 and APPDutch mice. APP23 mice were less impaired (red: Arc mRNA; green: Aβ; blue: DAPI). Scale bar = 200 μm. C: Stereological quantification of neocortical Arc mRNA-positive neurons revealed changes in the percentage of Arc mRNA positive neurons in relation to age-matched ntg controls. D: Changes in total number of Arc mRNA-positive neurons within the dentate gyrus compared with age-matched wild-type controls. C and D: Number of mice per group (ntg/tg): young APPPS1 (5/5); aged APPPS1 (5/5); young APPDutch (4/6); aged APPDutch (7/8); young APP23 (5/3); aged APP23 (7/6).
Figure 4
Figure 4
The decrease in total neocortical Arc mRNA levels was similar to the stereological results whereas synaptophysin mRNA expression is not reduced. A: Relative levels of Arc mRNA were detected via radioactive in situ hybridization. Representative pictures show the typical Arc activation pattern from aged animals of each line. No signal was observed with the sense Arc riboprobe. B: Quantification of the amount of neocortical Arc mRNA (mean intensity) in relation to age-matched ntg controls. C: Representative pictures illustrating neocortical synaptophysin mRNA expression. No signal was detected with the sense synaptophysin oligo probe. D: No significant changes in the relative levels of neocortical synaptophysin mRNA were obtained for any group in comparison with age-matched controls. B and D: Number of mice per group (ntg/tg): young APPPS1 (5/5); aged APPPS1 (5/5); young APPDutch (4/6); aged APPDutch (7/8); young APP23 (5/3); aged APP23 (7/6).
Figure 5
Figure 5
Vicinity to fibrillar Aβ and the presence of intracellular granular Aβ both reduce Arc mRNA expression. A: Example pictures of neurons neighboring fibrillar Aβ, either in form of a plaque (left; white arrowheads indicate a subset of the affected neuronal nuclei) or diffuse fibrillar Aβ (center). Image on the right illustrates a neuron showing intracellular granular Aβ. Scale bars: 20 μm (left); 10 μm (middle and right). red: Arc mRNA; green: Aβ; blue: DRAQ5. B: Arc intensity measurement around single neuronal nuclei revealed an overall reduction in tg control neurons (ie, those negative for the separately analyzed Aβ pathologies) compared with ntg neurons from wild-type mice. A further reduction was found for fibrillar neurons in close vicinity to plaques/diffuse Aβ. Neurons with intracellular granular Aβ showed no significant mean difference, which is explained by the Arc intensity distribution (percentile plot, lime green curve) in the overall neocortical analysis (baseline shift). In total 29 ntg and 31 tg mice were analyzed. **P < 0.01 C: Targeted analysis of Arc mRNA expression in individual layer V cortical neurons of young APPDutch (n = 6) and APP23 (n = 3) mice and age-matched ntg mice (n = 4 and 5). A significant difference in mean Arc intensity levels was found for tg versus ntg control neurons. Activated neurons were almost completely absent for the population of neurons containing Aβ granules.
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