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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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Experimental design.Control mice included wt and APPswe-PS1ΔE9 that received no irradiation or BMT and were euthanized at 5 and 13 months of age for analysis of retinal pathology. Additional control wt and APPswe-PS1ΔE9 mice received head only (HO) irradiation (XRT) at 5 months of age and were euthanized at 13 months of age for analysis of retinal pathology. Experimental groups included 5-month-old wt and APPswe-PS1ΔE9 mice that received lethal (10.5 Gy) whole body (WB) irradiation followed 24 hours later by retroorbital venous plexus injection of whole bone marrow from GFP-expressing wt mice and were then euthanized at 13 months of age for analysis of retinal pathology. Arrows mark the time points of generation and analysis of the control or treated mice.
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pone-0064246-g001: Experimental design.Control mice included wt and APPswe-PS1ΔE9 that received no irradiation or BMT and were euthanized at 5 and 13 months of age for analysis of retinal pathology. Additional control wt and APPswe-PS1ΔE9 mice received head only (HO) irradiation (XRT) at 5 months of age and were euthanized at 13 months of age for analysis of retinal pathology. Experimental groups included 5-month-old wt and APPswe-PS1ΔE9 mice that received lethal (10.5 Gy) whole body (WB) irradiation followed 24 hours later by retroorbital venous plexus injection of whole bone marrow from GFP-expressing wt mice and were then euthanized at 13 months of age for analysis of retinal pathology. Arrows mark the time points of generation and analysis of the control or treated mice.

Mentions: The experimental groups and manipulations are depicted graphically in Fig. 1. All procedures in this study were approved by the University of Washington Institutional Animal Care and Use Committee. Mice were originally obtained from Jackson Laboratories (Bar Harbor, ME) and bred in our colony. BMT were performed in female B6C3F1/J hemizygous APPswe-PS1ΔE9 transgenic mice and their wt littermate controls using male C57BL/6 mice hemizygous for enhanced green fluorescent protein (GFP) mice as donors. The APPswe transgene encodes a mouse-human hybrid transgene containing the mouse sequence in the extracellular and intracellular regions and a human sequence within the Aβ domain with Swedish mutations K594N and M595L [39], [40]. The PS1ΔE9 transgene encodes exon-9-deleted human presenilin-1. Both transgenes are co-expressed under control of the mouse prion promoter with plaque deposition beginning at 5 months of age [39], [40]. GFP expression is under control of the β-actin promoter and cytomegalovirus enhancer.


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)

Experimental design.Control mice included wt and APPswe-PS1ΔE9 that received no irradiation or BMT and were euthanized at 5 and 13 months of age for analysis of retinal pathology. Additional control wt and APPswe-PS1ΔE9 mice received head only (HO) irradiation (XRT) at 5 months of age and were euthanized at 13 months of age for analysis of retinal pathology. Experimental groups included 5-month-old wt and APPswe-PS1ΔE9 mice that received lethal (10.5 Gy) whole body (WB) irradiation followed 24 hours later by retroorbital venous plexus injection of whole bone marrow from GFP-expressing wt mice and were then euthanized at 13 months of age for analysis of retinal pathology. Arrows mark the time points of generation and analysis of the control or treated mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672108&req=5

pone-0064246-g001: Experimental design.Control mice included wt and APPswe-PS1ΔE9 that received no irradiation or BMT and were euthanized at 5 and 13 months of age for analysis of retinal pathology. Additional control wt and APPswe-PS1ΔE9 mice received head only (HO) irradiation (XRT) at 5 months of age and were euthanized at 13 months of age for analysis of retinal pathology. Experimental groups included 5-month-old wt and APPswe-PS1ΔE9 mice that received lethal (10.5 Gy) whole body (WB) irradiation followed 24 hours later by retroorbital venous plexus injection of whole bone marrow from GFP-expressing wt mice and were then euthanized at 13 months of age for analysis of retinal pathology. Arrows mark the time points of generation and analysis of the control or treated mice.
Mentions: The experimental groups and manipulations are depicted graphically in Fig. 1. All procedures in this study were approved by the University of Washington Institutional Animal Care and Use Committee. Mice were originally obtained from Jackson Laboratories (Bar Harbor, ME) and bred in our colony. BMT were performed in female B6C3F1/J hemizygous APPswe-PS1ΔE9 transgenic mice and their wt littermate controls using male C57BL/6 mice hemizygous for enhanced green fluorescent protein (GFP) mice as donors. The APPswe transgene encodes a mouse-human hybrid transgene containing the mouse sequence in the extracellular and intracellular regions and a human sequence within the Aβ domain with Swedish mutations K594N and M595L [39], [40]. The PS1ΔE9 transgene encodes exon-9-deleted human presenilin-1. Both transgenes are co-expressed under control of the mouse prion promoter with plaque deposition beginning at 5 months of age [39], [40]. GFP expression is under control of the β-actin promoter and cytomegalovirus enhancer.

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