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. 2015 Nov 11:3:71.
doi: 10.1186/s40478-015-0251-x.

Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer's disease lacking functional B and T cells

Claudia Späni  1   2 , Tobias Suter  3   2 , Rebecca Derungs  1   2 , Maria Teresa Ferretti  1   2 , Tobias Welt  1 , Fabian Wirth  1   2 , Christoph Gericke  1   2 , Roger M Nitsch  1   2 , Luka Kulic  4   5   6
Affiliations

Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer's disease lacking functional B and T cells

Claudia Späni et al. Acta Neuropathol Commun. .

Abstract

Introduction: In Alzheimer's disease, accumulation and pathological aggregation of amyloid β-peptide is accompanied by the induction of complex immune responses, which have been attributed both beneficial and detrimental properties. Such responses implicate various cell types of the innate and adaptive arm of the immunesystem, both inside the central nervous system, and in the periphery. To investigate the role of the adaptive immune system in brain β-amyloidosis, PSAPP transgenic mice, an established mouse model of Alzheimer's disease, were crossbred with the recombination activating gene-2 knockout (Rag2 ko) mice lacking functional B and T cells. In a second experimental paradigm, aged PSAPP mice were reconstituted with bone marrow cells from either Rag2 ko or wildtype control mice.

Results: Analyses from both experimental approaches revealed reduced β-amyloid pathology and decreased brain amyloid β-peptide levels in PSAPP mice lacking functional adaptive immune cells. The decrease in brain β-amyloid pathology was associated with enhanced microgliosis and increased phagocytosis of amyloid β-peptide aggregates.

Conclusion: The results of this study demonstrate an impact of the adaptive immunity on cerebral β-amyloid pathology in vivo and suggest an influence on microglia-mediated amyloid β-peptide clearance as a possible underlying mechanism.

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Figures

Fig. 1
Fig. 1
Reduced amyloid pathology and reduced Aβ levels in 8 month-old PSAPP/Rag2 ko mice in comparison to age-matched PSAPP mice. a, b Quantitative analysis of Thioflavin S stainings shows a 25 % reduction in amyloid load and amyloid plaque number in the B and T cell-ablated PSAPP/Rag2 ko mice as compared to the PSAPP mice with a functional adaptive immune system (representative images of cortical stainings are shown in (a)). Scale bar = 300 μm. ***p < 0.001. n = 13–15 per group. c Quantitative MSD analysis of Aβ40 and Aβ42 in plasma and cortical brain extracts shows a significant reduction in Tris soluble, SDS detergent soluble and formic acid soluble Aβ40 and Aβ42 levels in the PSAPP/Rag2 ko mice as compared to the PSAPP mice. The reduction in brain Aβ levels is accompanied by a significant increase in plasma Aβ42. *p < 0.05. **p < 0.01. ***p < 0.001. n = 9–14 per group
Fig. 2
Fig. 2
Glial responses in the absence of functional B and T cells at 8 months. a, b GFAP immunohistological analysis for astrocytes and (c, d) Iba1 immunostaining for microglia reveal significant increases in microgliosis in the amyloid-depositing APP transgenic mice (PSAPP/Rag2 ko and PSAPP) in comparison to the non-transgenic Rag2 ko and WT mice. GFAP immunoreactivity (b) – but not Iba1 immunoreactivity (d) – is significantly reduced in the PSAPP/Rag2 ko mice as compared to the PSAPP mice (representative images of cortical stainings are shown on the left). Scale bar = 300 μm (Insert: Scale bar = 40 μm). *p < 0.05. ***p < 0.001. n = 10–14 per group
Fig. 3
Fig. 3
Impaired hippocampal memory performance in the PSAPP transgenic mice and both Rag2 ko-deficient mouse lines in comparison to the WT control. a Y maze performance was evaluated by correct alternations in %. b Recognition memory in the novel object recognition task (NORT) was measured by comparing the time spent with the novel and the familiar object. In the Y maze and the novel object recognition task performance was compared to chance level (50 % and 1, respectively). Significant differences are shown. *p < 0.05. n = 9–21 per group
Fig. 4
Fig. 4
Bone marrow (BM) transfer experiment. a 12 month-old PSAPP mice (immunophenotype H2b, CD45.2) were lethally irradiated with two doses of 600 rads, then reconstituted with 5 x 106 BM cells from either Rag2 ko or WT donor mice (immunophenotype H2b, CD45.1). b 6 months after transplantation, Rag2 ko BM recipients showed a fivefold reduction in B cells and CD4+ T cells, as determined by FACS staining of CD45+ blood leukocytes with antibodies against CD4 and the pan B-cell marker B220. **p < 0.01. ***p < 0.001 . n = 9–10 per group
Fig. 5
Fig. 5
Reduced Aβ load in PSAPP mice reconstituted with Rag2 ko BM a, b). Quantitative analysis of free-floating sections stained with the monoclonal anti-Aβ antibody 6E10 shows a 35 % reduction in the Aβ-immunoreactivity, but no significant change in Aβ-immunoreactive plaque number, in Rag2 ko BM-transferred PSAPP mice as compared to WT BM-transferred PSAPP mice 6 months after reconstitution (at 18 months of age; representative images of cortical stainings are shown in (a)). Scale bar = 300 μm. *p < 0.05. n = 8–10 per group. (c) Quantitative MSD analysis of plasma and cortical brain extracts reveals a significant reduction in formic acid soluble Aβ40 and Aβ42 along with an increase in plasma Aβ levels in PSAPP mice transferred with Rag2 ko BM in comparison with WT BM-transferred PSAPP mice. *p < 0.05. n = 9–10 per group
Fig. 6
Fig. 6
Glial responses in PSAPP mice reconstituted with WT and Rag2 ko BM. a Astrogliosis is unchanged in Rag2 ko BM-transferred mice in comparison to WT BM-transferred PSAPP mice 6 months after reconstitution (at 18 months; representative images of cortical stainings are shown on the left). b Quantitative analysis of GFAP immunostainings. c, d Iba1 immunohistological analysis reveals a significant increase in microgliosis in Rag2 ko BM-recipient PSAPP mice in comparison to WT BM-transferred PSAPP mice. Scale bar = 300 μm (Insert: Scale bar = 40 μm). *p < 0.05. n = 8–10 per group
Fig. 7
Fig. 7
Increased number of Aβ-phagocytosing microglia in the Rag2 ko BM-reconstituted PSAPP mice. a Representative maximum projection confocal image (left panel) of a plaque-associated microglial cell containing Thioflavin S-positive Aβ material (arrowhead). Image shows microglia (Iba1, red) and amyloid deposits (Thioflavin S, green). Nuclei were counterstained by DAPI (blue). Orthogonal views of z-stack images are shown in the right panel. Scale bar = 20 μm (b) significantly increased number of amyloid plaque-associated Iba1-positive microglial cells containing Thioflavin S-positive Aβ material in the Rag2 ko BM-recipient PSAPP mice. *p < 0.05. n = 9 mice per group (on average 12 plaques per mouse analyzed) (c) significantly increased total volume of phagocytosed Aβ material in the Rag2 ko BM-reconstituted PSAPP mice in comparison to the WT BM-recipient control mice. *p < 0.05. n = 9 mice per group (on average 12 plaques per mouse analyzed)
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