Abundance of Aβ5-x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease

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Abstract

Background: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptide (Aβ) within neurons. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that Aβx-42 isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and Aβx-42 species have been pointed as crucial players in AD etiology, the Aβ5-x isoforms have not received much attention. Results: The present study is the first to show immunohistochemical evidence of Aβ5-x in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe Aβ5-x peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of Aβ5-x distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular Aβ deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal Aβ5-x. Conclusions: Different degrees of Aβ5-x accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular Aβ5-x, these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher Aβ5-x-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving Aβ5-x peptides and operating in a divergent way in the late and early onset forms of the disease. © 2014 Guzmán et al.; licensee BioMed Central Ltd.

Figures

  • Table 1 Demographic data and semiquantitative analysis of antibody stainings in SAD, FAD and non-demented control cases
  • Figure 1 Analysis of the AB5-3 using dot blotting. Full length and N-truncated amyloid-β peptides were probed and spotted into a nitrocellulose membrane. (A) After incubation with the primary antibody AB5-3 only the Aβ5–42 variant was recognized indicating specificity for this peptide. (B) The pan-Aβ antibody 24311 recognized all Aβ variants demonstrating that all peptides were available.
  • Figure 2 SDS-PAGE Western blot analysis of the AB5-3 and pan-Aβ 4G probed to a membrane. (A) The polyclonal AB5-3 antibody detects Aβ5–42 tr detects different sizes of all Aβ species.
  • Figure 3 Immunohistochemical staining pattern of Aβ5-X in cortex of sporadic AD human brain. Vascular Aβ5-x immunoreactivity (A, E, F) was detected in the majority of the SAD cases analyzed in hippocampus (A) and cerebral cortex (E), whereas extracellular Aβ5-x-positive deposits (C, G, H) were less abundant in both brain areas (C, D). The pan-Aβ antibody 24311 (B, D) demonstrates cerebral amyloid angiopathy (CAA) and plaque load (arrows). The same cortical region stained in a parallel section with the AB5-3 antibody (F, H) binds preferentially to blood vessels presenting CAA and barely recognizes plaques. Scale bar: 50 μm.
  • Figure 4 Immunohistochemical staining pattern of Aβ5-x in cortex of familial AD human brain. Vascular and parenchymal Aβ5-x-positive deposits were detected in parallel sections obtained from FAD cases including subjects with the Arctic (A) and Swedish mutations (C) in contrast to abundant 4G8-immuoreactivity in both cases (B, D). Sections of a PS1ΔE9 mutation carrier probed with the AB5-3 antibody (E) showed equal or higher vascular Aβ5-x-immunoreactivity compared to Aβ42 (F) whereas the Aβ5-x-parenchymal deposits were detected with lower intensity. Scale bar: 200 μm.
  • Table 2 Transgenic AD-like mouse models in which Aβ5-x dep
  • Figure 5 Immunohistochemical staining pattern of Aβ5-x in aged APP/PS1KI, 5XFAD and 3xTg transgenic mice. Parenchymal Aβ5-x extracellular deposits were detected with the AB5-3 polyclonal antibody in the APP/PS1K1 (A-D), 5XFAD (F-I) and 3xTg on hippocampus (E) and medulla (J). Larger regions were affected with plaques on hippocampus (A, F), cortex (B, G), thalamus (C, H) and piriform cortex (D, I) in the first two mouse models. Scale bar: 50 μm.
  • Figure 6 Analysis of consecutive sections of AD mouse models using detected in hippocampal brain sections of the 3xTg (A, D), 5XFAD (B, E) a antibody and the 24311 pan-Aβ antibody. Parallel sections reveal Aβ5-x imm same amyloid plaque detected by the two different antibodies). Scale bar:

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APA

Guzmán, E. A., Bouter, Y., Richard, B. C., Lannfelt, L., Ingelsson, M., Paetau, A., … Bayer, T. A. (2014). Abundance of Aβ5-x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer’s disease. Molecular Neurodegeneration, 9(1). https://doi.org/10.1186/1750-1326-9-13

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