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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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RGCL neuroprotection is not due to effects of high dose cranial irradiation alone.A: Representative photographs of control mice (no Tx) and mice that received head only irradiation (HO-XRT) demonstrate effects of irradiation on coat color and confirm radiation exposure in HO-XRT mice (top). Representative photomicrographs of NeuN+ neurons (red) in RGCL stained with NeuN antibody and visualized with Cy3-conjugated secondary antibody show a mild reduction in neuron density 8 months after HO-XRT (bottom). Scale bar  = 50 μm. B: Quantification of neuron density depicted as a percent of age-matched, non-irradiated wt controls demonstrates there is a mild reduction in RGCL neurons as a result of high dose irradiation without BMT in wt and APPswe-PS1ΔE9 mice, thus eliminating the possibility that high dose cranial irradiation underlies the neuroprotective effects of BMT.
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pone-0064246-g006: RGCL neuroprotection is not due to effects of high dose cranial irradiation alone.A: Representative photographs of control mice (no Tx) and mice that received head only irradiation (HO-XRT) demonstrate effects of irradiation on coat color and confirm radiation exposure in HO-XRT mice (top). Representative photomicrographs of NeuN+ neurons (red) in RGCL stained with NeuN antibody and visualized with Cy3-conjugated secondary antibody show a mild reduction in neuron density 8 months after HO-XRT (bottom). Scale bar  = 50 μm. B: Quantification of neuron density depicted as a percent of age-matched, non-irradiated wt controls demonstrates there is a mild reduction in RGCL neurons as a result of high dose irradiation without BMT in wt and APPswe-PS1ΔE9 mice, thus eliminating the possibility that high dose cranial irradiation underlies the neuroprotective effects of BMT.

Mentions: Previous studies in our lab demonstrated that high dose cranial irradiation is not sufficient to reduce the accumulation of Aβ peptides or plaques in APPswe-PS1ΔE9 mice cerebrum [32]. In order to exclude an effect of high dose cranial irradiation in the observed protection of retina, we exposed 5-month-old wt and APPswe-PS1ΔE9 mice to the same dose of irradiation given to BMT recipients (10.5 Gy) but shielded the body from the neck to the tip of the tail. These “head only” irradiated mice did not receive BMT and were euthanized 8 months post-irradiation at 13 months of age. Grayish discoloration of the fur in irradiated mice confirmed complete cranial irradiation to the exclusion of the rest of the body (Fig. 6A). Quantification of NeuN+ cells was performed in a manner identical to previous experiments (Fig. 4) and revealed mildly reduced NeuN+ RGCL neurons in wt and APPswe-PS1ΔE9 mice that received cranial irradiation compared with non-irradiated controls (Fig. 6A and 6B). While others have recently demonstrated neuroprotective effects of irradiation in experimental glaucoma [53], [54] and retinitis pigmentosa [55], and evidence of irradiation-induced RGCL neuron toxicity is relatively limited to developing retina [56], [57], [58], [59], we believe this is the first study to show no protective effect of irradiation in normal aging and experimental AD.


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)

RGCL neuroprotection is not due to effects of high dose cranial irradiation alone.A: Representative photographs of control mice (no Tx) and mice that received head only irradiation (HO-XRT) demonstrate effects of irradiation on coat color and confirm radiation exposure in HO-XRT mice (top). Representative photomicrographs of NeuN+ neurons (red) in RGCL stained with NeuN antibody and visualized with Cy3-conjugated secondary antibody show a mild reduction in neuron density 8 months after HO-XRT (bottom). Scale bar  = 50 μm. B: Quantification of neuron density depicted as a percent of age-matched, non-irradiated wt controls demonstrates there is a mild reduction in RGCL neurons as a result of high dose irradiation without BMT in wt and APPswe-PS1ΔE9 mice, thus eliminating the possibility that high dose cranial irradiation underlies the neuroprotective effects of BMT.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0064246-g006: RGCL neuroprotection is not due to effects of high dose cranial irradiation alone.A: Representative photographs of control mice (no Tx) and mice that received head only irradiation (HO-XRT) demonstrate effects of irradiation on coat color and confirm radiation exposure in HO-XRT mice (top). Representative photomicrographs of NeuN+ neurons (red) in RGCL stained with NeuN antibody and visualized with Cy3-conjugated secondary antibody show a mild reduction in neuron density 8 months after HO-XRT (bottom). Scale bar  = 50 μm. B: Quantification of neuron density depicted as a percent of age-matched, non-irradiated wt controls demonstrates there is a mild reduction in RGCL neurons as a result of high dose irradiation without BMT in wt and APPswe-PS1ΔE9 mice, thus eliminating the possibility that high dose cranial irradiation underlies the neuroprotective effects of BMT.
Mentions: Previous studies in our lab demonstrated that high dose cranial irradiation is not sufficient to reduce the accumulation of Aβ peptides or plaques in APPswe-PS1ΔE9 mice cerebrum [32]. In order to exclude an effect of high dose cranial irradiation in the observed protection of retina, we exposed 5-month-old wt and APPswe-PS1ΔE9 mice to the same dose of irradiation given to BMT recipients (10.5 Gy) but shielded the body from the neck to the tip of the tail. These “head only” irradiated mice did not receive BMT and were euthanized 8 months post-irradiation at 13 months of age. Grayish discoloration of the fur in irradiated mice confirmed complete cranial irradiation to the exclusion of the rest of the body (Fig. 6A). Quantification of NeuN+ cells was performed in a manner identical to previous experiments (Fig. 4) and revealed mildly reduced NeuN+ RGCL neurons in wt and APPswe-PS1ΔE9 mice that received cranial irradiation compared with non-irradiated controls (Fig. 6A and 6B). While others have recently demonstrated neuroprotective effects of irradiation in experimental glaucoma [53], [54] and retinitis pigmentosa [55], and evidence of irradiation-induced RGCL neuron toxicity is relatively limited to developing retina [56], [57], [58], [59], we believe this is the first study to show no protective effect of irradiation in normal aging and experimental AD.

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