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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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Schematic representation of the mechanism of BMT-mediated neuroprotection in neurodegeneration of inner retina.Endogenous microglia (right side) have a pro-inflammatory phenotype that results in impaired phagocytosis of Aβ and increased elaboration of ROS, resulting in increased neurotoxicity. In contrast, BM-derived peripheral blood monocytes migrate into the retina through the blood retinal barrier, and then differentiate into microglia characterized by MHC class II expression. This altered molecular phenotype mediates increased clearance of Aβ and reduced elaboration of neurotoxic ROS.
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pone-0064246-g009: Schematic representation of the mechanism of BMT-mediated neuroprotection in neurodegeneration of inner retina.Endogenous microglia (right side) have a pro-inflammatory phenotype that results in impaired phagocytosis of Aβ and increased elaboration of ROS, resulting in increased neurotoxicity. In contrast, BM-derived peripheral blood monocytes migrate into the retina through the blood retinal barrier, and then differentiate into microglia characterized by MHC class II expression. This altered molecular phenotype mediates increased clearance of Aβ and reduced elaboration of neurotoxic ROS.

Mentions: We hypothesize that BMT results in reduced oxidative stress and mitigates neurotoxicity, possibly through MHC class II related pathways. RGCL neuron apoptosis is associated with increased production of Aβ and is reversed by inhibition of Aβ formation and aggregation [22]. Further, Aβ-induced chronic activation of glial cells results in progressive atrophy of retinal neurons in vivo[77] and Aβ has been shown to damage neurons by stimulating inflammation and microglia activation [78], [79]. Finally, activated microglia cells express neurotoxic cytokines and small reactive molecules, including ROS, which cause RGC degeneration. We suggest a pathogenic mechanism in which age-related neurotoxicity [80] is exacerbated by Aβ peptide deposition, and MHC class II expressing BMT-derived microglia suppress this response (Fig. 9). Studies to further elucidate differences between endogenous and donor-derived microglia will be critical to developing future microglia based therapies for neurodegenerative disease.


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)

Schematic representation of the mechanism of BMT-mediated neuroprotection in neurodegeneration of inner retina.Endogenous microglia (right side) have a pro-inflammatory phenotype that results in impaired phagocytosis of Aβ and increased elaboration of ROS, resulting in increased neurotoxicity. In contrast, BM-derived peripheral blood monocytes migrate into the retina through the blood retinal barrier, and then differentiate into microglia characterized by MHC class II expression. This altered molecular phenotype mediates increased clearance of Aβ and reduced elaboration of neurotoxic ROS.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0064246-g009: Schematic representation of the mechanism of BMT-mediated neuroprotection in neurodegeneration of inner retina.Endogenous microglia (right side) have a pro-inflammatory phenotype that results in impaired phagocytosis of Aβ and increased elaboration of ROS, resulting in increased neurotoxicity. In contrast, BM-derived peripheral blood monocytes migrate into the retina through the blood retinal barrier, and then differentiate into microglia characterized by MHC class II expression. This altered molecular phenotype mediates increased clearance of Aβ and reduced elaboration of neurotoxic ROS.
Mentions: We hypothesize that BMT results in reduced oxidative stress and mitigates neurotoxicity, possibly through MHC class II related pathways. RGCL neuron apoptosis is associated with increased production of Aβ and is reversed by inhibition of Aβ formation and aggregation [22]. Further, Aβ-induced chronic activation of glial cells results in progressive atrophy of retinal neurons in vivo[77] and Aβ has been shown to damage neurons by stimulating inflammation and microglia activation [78], [79]. Finally, activated microglia cells express neurotoxic cytokines and small reactive molecules, including ROS, which cause RGC degeneration. We suggest a pathogenic mechanism in which age-related neurotoxicity [80] is exacerbated by Aβ peptide deposition, and MHC class II expressing BMT-derived microglia suppress this response (Fig. 9). Studies to further elucidate differences between endogenous and donor-derived microglia will be critical to developing future microglia based therapies for neurodegenerative disease.

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