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Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer's disease - PubMed

  • ️Wed Jan 01 2014

Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer's disease

Sonia George et al. Acta Neuropathol Commun. 2014.

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Abstract

Background: The progressive development of Alzheimer's disease (AD) pathology follows a spatiotemporal pattern in the human brain. In a transgenic (Tg) mouse model of AD expressing amyloid precursor protein (APP) with the arctic (E693G) mutation, pathology spreads along anatomically connected structures. Amyloid-β (Aβ) pathology first appears in the subiculum and is later detected in interconnected brain regions, including the retrosplenial cortex. We investigated whether the spatiotemporal pattern of Aβ pathology in the Tg APP arctic mice to interconnected brain structures can be interrupted by destroying neurons using a neurotoxin and thereby disconnecting the neural circuitry.

Results: We performed partial unilateral ibotenic acid lesions of the subiculum (first structure affected by Aβ pathology) in young Tg APParc mice, prior to the onset of pathology. We assessed Aβ/C99 pathology in mice aged up to 6 months after injecting ibotenate into the subiculum. Compared to the brains of intact Tg APP arctic mice, we observed significantly decreased Aβ/C99 pathology in the ipsilateral dorsal subiculum, CA1 region of the hippocampus and the retrosplenial cortex; regions connecting to and from the dorsal subiculum. By contrast, Aβ/C99 pathology was unchanged in the contralateral hippocampus in the mice with lesions.

Conclusion: These results, obtained in an animal model of AD, support the notion that Aβ/C99 pathology is transmitted between interconnected neurons in AD.

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Figures

Figure 1
Figure 1

Illustration of the progressive diffuse amyloid deposition in homozygous TgAPParc mice with altered pathology following subiculum lesion. Anatomical connections between brain regions are marked by arrows. Colored text indicates the age when the first diffuse amyloid deposits are detected in the respective brain regions. Syringe marks the site of ibotenic acid lesion. Amyloid deposition affects functionally connected brain regions sequentially from the subiculum and brain structures receiving input from subiculum including the retrosplenial cortex, mammillary body, and thalamus. Decreased Aβ/C99 pathology was observed in the subiculum, CA1 and RSG (indicated). Schematic modified from Rönnback et al., 2012 [7], with permission.

Figure 2
Figure 2

Aβ/C99 immunoreactivity in dorsal subiculum, CA1 and RSG of Tg APParc mice that have undergone partial destruction of the subiculum. A. Tg APParc mice aged 3 months comparing lesioned and intact hemispheres in the dorsal subiculum and CA1 of Tg mice injected with PBS (TG + PBS), Tg mice injected with ibotenic acid (TG + Ibo) and WT mice injected with ibotenic acid (WT + Ibo). We observed decreased Aβ pathology in both the dorsal subiculum and CA1 in Tg mice injected with ibotenic acid (Tg + Ibo). B. Aβ/C99 immunoreactivity in dorsal subiculum, CA1 and RSG of lesioned Tg APParc mice aged 6 months. Tg mice with ibotenic acid lesions have decreased Aβ/C99 immunoreactivity in the dorsal subiculum, CA1 and RSG. C. Quantification of the Aβ/C99 immunoreactivity comparing Aβ/C99 immunoreactivity (Aβ IR) in the lesioned hemisphere as a percentage of the contralateral side. Tg mice with ibotenic acid lesions have significantly decreased Aβ/C99 immunoreactivity in the damaged hemisphere in the dorsal subiculum and CA1 at ages 3 and 6 months. D. Plots representing cell count in the subiculum (percentage of contralateral side) vs. Aβ/C99 immunoreactivity in Tg + Ibo animals for the dorsal subiculum, CA1 and RSG of mice aged 3 and 6 months. Plots indicate a no correlation, rs = 0.2, p > 0.05 (3 and 6 months dorsal subiculum, CA1 and RSG). Data expressed as means ± SEM. Asterisk denotes statistical significance (*p < 0.05).

Figure 3
Figure 3

Cell counts in the dorsal subiculum, CA1 and RSG of lesioned Tg APParc mice aged 3 and 6 months. A. Representative images of cresyl violet stained tissue of Tg APParc mice aged 6 months comparing lesioned and intact hemispheres in the dorsal subiculum, CA1 and RSG of Tg mice injected with PBS (Tg + PBS), Tg mice injected with ibotenic acid (TG + Ibo) and WT mice injected with ibotenate (WT + Ibo). B. Quantification of cell counts comparing the percentage cell loss to the contralateral side. Data expressed as means ± SEM. Asterisk denotes statistical significance (*p < 0.05). CA1 and RSG (indicated).

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References

    1. Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA, Schwarz RD, Roher AE, Walker LC. Evidence for seeding of β-amyloid by intracerebral infusion of Alzheimer brain extracts in β-amyloid precursor protein-transgenic mice. J Neurosci. 2000;2:3606–3611. - PMC - PubMed
    1. Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol. 2011;2:532–540. doi: 10.1002/ana.22615. - DOI - PMC - PubMed
    1. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, Ghetti B, Goedert M, Tolnay M. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci. 2013;2:9535–9540. doi: 10.1073/pnas.1301175110. - DOI - PMC - PubMed
    1. Clavaguera F, Lavenir I, Falcon B, Frank S, Goedert M, Tolnay M. “Prion-like” templated misfolding in tauopathies. Brain Pathol. 2013;2:342–349. doi: 10.1111/bpa.12044. - DOI - PMC - PubMed
    1. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;2:909–913. doi: 10.1038/ncb1901. - DOI - PMC - PubMed

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