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Suppressed retinal degeneration in aged wild type and APPswe/PS1ΔE9 mice by bone marrow transplantation.

Yang Y, Shiao C, Hemingway JF, Jorstad NL, Shalloway BR, Chang R, Keene CD - PLoS ONE (2013)

Bottom Line: BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels.Interestingly, aged wt BMT recipients also had significantly more neurons (25.4%) compared with non-transplanted aged wt controls.We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.

ABSTRACT
Alzheimer's disease (AD) is an age-related condition characterized by accumulation of neurotoxic amyloid β peptides (Aβ) in brain and retina. Because bone marrow transplantation (BMT) results in decreased cerebral Aβ in experimental AD, we hypothesized that BMT would mitigate retinal neurotoxicity through decreased retinal Aβ. To test this, we performed BMT in APPswe/PS1ΔE9 double transgenic mice using green fluorescent protein expressing wild type (wt) mice as marrow donors. We first examined retinas from control, non-transplanted, aged AD mice and found a two-fold increase in microglia compared with wt mice, prominent inner retinal Aβ and paired helical filament-tau, and decreased retinal ganglion cell layer neurons. BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels. Aβ and paired helical filament-tau were reduced (61.0% and 44.1% respectively) in BMT-recipient AD mice, which had 20.8% more retinal ganglion cell layer neurons than non-transplanted AD controls. Interestingly, aged wt BMT recipients also had significantly more neurons (25.4%) compared with non-transplanted aged wt controls. Quantitation of retinal ganglion cell layer neurons in young mice confirmed age-related retinal degeneration was mitigated by BMT. We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons. Thus, BMT is neuroprotective in age-related as well as AD-related retinal degeneration, and may be a result of alterations in innate immune function and oxidative stress in BMT recipient mice.

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Age-related RGCL neurodegeneration is mitigated by BMT in wt and APPswe-PS1ΔE9 mice.NeuN+ RGCL neuron density was compared between 13-month-old BMT recipient mice and non-transplanted young (5 mo) and age-matched (13 mo) wt and APPswe-PS1ΔE9 mice and presented as percent of 5-month-old wt non-transplanted controls. There was a significant age-dependent reduction in neuron density that was partially rescued in wt and APPswe-PS1ΔE9 BMT recipient mice. ***P<0.001, #P<0.05, ##P<0.01, n = 6–10, two-way ANOVA followed by Bonferroni post test.
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pone-0064246-g005: Age-related RGCL neurodegeneration is mitigated by BMT in wt and APPswe-PS1ΔE9 mice.NeuN+ RGCL neuron density was compared between 13-month-old BMT recipient mice and non-transplanted young (5 mo) and age-matched (13 mo) wt and APPswe-PS1ΔE9 mice and presented as percent of 5-month-old wt non-transplanted controls. There was a significant age-dependent reduction in neuron density that was partially rescued in wt and APPswe-PS1ΔE9 BMT recipient mice. ***P<0.001, #P<0.05, ##P<0.01, n = 6–10, two-way ANOVA followed by Bonferroni post test.

Mentions: It was clear that BMT-mediated neuroprotection was present in both wt and APPswe-PS1ΔE9 mice. We hypothesized that this neuroprotection may be a result of decreased age-related neurotoxicity based on a recent study of human retina that identified significant loss of RGCs in aged vs. young retinas [2]. To test this possibility, we examined retinas from young (5-month-old) wt and APPswe-PS1ΔE9 mice and found approximately 40% more RGCL neurons in eyes from young mice of both genotypes compared with 13-month-old wt and APPswe-PS1ΔE9 controls in the absence of transplantation, irradiation, or other manipulations (Fig. 5, P<0.001, two-way ANOVA Bonferroni post test). Our data suggest that the neuroprotective effects of BMT target age-related RGCL neuron loss independent of Aβ, and that BMT provides added protection against Aβ-mediated loss of inner retinal neuropil.


Suppressed retinal degeneration in aged wild type and APPswe/PS1ΔE9 mice by bone marrow transplantation.

Yang Y, Shiao C, Hemingway JF, Jorstad NL, Shalloway BR, Chang R, Keene CD - PLoS ONE (2013)

Age-related RGCL neurodegeneration is mitigated by BMT in wt and APPswe-PS1ΔE9 mice.NeuN+ RGCL neuron density was compared between 13-month-old BMT recipient mice and non-transplanted young (5 mo) and age-matched (13 mo) wt and APPswe-PS1ΔE9 mice and presented as percent of 5-month-old wt non-transplanted controls. There was a significant age-dependent reduction in neuron density that was partially rescued in wt and APPswe-PS1ΔE9 BMT recipient mice. ***P<0.001, #P<0.05, ##P<0.01, n = 6–10, two-way ANOVA followed by Bonferroni post test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672108&req=5

pone-0064246-g005: Age-related RGCL neurodegeneration is mitigated by BMT in wt and APPswe-PS1ΔE9 mice.NeuN+ RGCL neuron density was compared between 13-month-old BMT recipient mice and non-transplanted young (5 mo) and age-matched (13 mo) wt and APPswe-PS1ΔE9 mice and presented as percent of 5-month-old wt non-transplanted controls. There was a significant age-dependent reduction in neuron density that was partially rescued in wt and APPswe-PS1ΔE9 BMT recipient mice. ***P<0.001, #P<0.05, ##P<0.01, n = 6–10, two-way ANOVA followed by Bonferroni post test.
Mentions: It was clear that BMT-mediated neuroprotection was present in both wt and APPswe-PS1ΔE9 mice. We hypothesized that this neuroprotection may be a result of decreased age-related neurotoxicity based on a recent study of human retina that identified significant loss of RGCs in aged vs. young retinas [2]. To test this possibility, we examined retinas from young (5-month-old) wt and APPswe-PS1ΔE9 mice and found approximately 40% more RGCL neurons in eyes from young mice of both genotypes compared with 13-month-old wt and APPswe-PS1ΔE9 controls in the absence of transplantation, irradiation, or other manipulations (Fig. 5, P<0.001, two-way ANOVA Bonferroni post test). Our data suggest that the neuroprotective effects of BMT target age-related RGCL neuron loss independent of Aβ, and that BMT provides added protection against Aβ-mediated loss of inner retinal neuropil.

Bottom Line: BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels.Interestingly, aged wt BMT recipients also had significantly more neurons (25.4%) compared with non-transplanted aged wt controls.We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.

ABSTRACT
Alzheimer's disease (AD) is an age-related condition characterized by accumulation of neurotoxic amyloid β peptides (Aβ) in brain and retina. Because bone marrow transplantation (BMT) results in decreased cerebral Aβ in experimental AD, we hypothesized that BMT would mitigate retinal neurotoxicity through decreased retinal Aβ. To test this, we performed BMT in APPswe/PS1ΔE9 double transgenic mice using green fluorescent protein expressing wild type (wt) mice as marrow donors. We first examined retinas from control, non-transplanted, aged AD mice and found a two-fold increase in microglia compared with wt mice, prominent inner retinal Aβ and paired helical filament-tau, and decreased retinal ganglion cell layer neurons. BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels. Aβ and paired helical filament-tau were reduced (61.0% and 44.1% respectively) in BMT-recipient AD mice, which had 20.8% more retinal ganglion cell layer neurons than non-transplanted AD controls. Interestingly, aged wt BMT recipients also had significantly more neurons (25.4%) compared with non-transplanted aged wt controls. Quantitation of retinal ganglion cell layer neurons in young mice confirmed age-related retinal degeneration was mitigated by BMT. We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons. Thus, BMT is neuroprotective in age-related as well as AD-related retinal degeneration, and may be a result of alterations in innate immune function and oxidative stress in BMT recipient mice.

Show MeSH
Related in: MedlinePlus