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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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BMT mediates neuroprotection of RGCL neurons in APPswe-PS1ΔE9 and wt mice.A–C: RGCL neurons were identified using anti-NeuN antibody and visualized with Cy3-conjugated secondary antibody in 13-month-old APPswe-PS1ΔE9 and wt mice. Representative photomicrographs of NeuN+ RGCL neurons in control (A, top) and BMT-recipient (A, bottom) APPswe-PS1ΔE9 mice demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (B) and inner retinal (NFL+RGCL+IPL) thickness (C). D–E: Representative photomicrographs of NeuN+ RGCL neurons in 13-month-old control (D, top) and BMT-recipient (D, bottom) wt mice also demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (E). F: No effects on retinal thickness in wt recipients compared with the wt controls. *P<0.05, n = 6–10, student's t test. Scale bar  = 50 μm.
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pone-0064246-g004: BMT mediates neuroprotection of RGCL neurons in APPswe-PS1ΔE9 and wt mice.A–C: RGCL neurons were identified using anti-NeuN antibody and visualized with Cy3-conjugated secondary antibody in 13-month-old APPswe-PS1ΔE9 and wt mice. Representative photomicrographs of NeuN+ RGCL neurons in control (A, top) and BMT-recipient (A, bottom) APPswe-PS1ΔE9 mice demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (B) and inner retinal (NFL+RGCL+IPL) thickness (C). D–E: Representative photomicrographs of NeuN+ RGCL neurons in 13-month-old control (D, top) and BMT-recipient (D, bottom) wt mice also demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (E). F: No effects on retinal thickness in wt recipients compared with the wt controls. *P<0.05, n = 6–10, student's t test. Scale bar  = 50 μm.

Mentions: Retinal neuronal degeneration is associated with Aβ deposition in AD [47], [48] and loss of retinal neurons in GCL has been demonstrated in both clinical and experimental AD [9], [49]. We hypothesized that BMT-mediated Aβ reduction would result in neuroprotection in retina, so we evaluated RGCL neuron survival in non-transplanted and BMT recipient APPswe-PS1ΔE9 mice using immunofluorescence. Representative photomicrographs of RGCL of age-matched control (Fig. 4A, upper panel) and 13-month-old BMT-recipient (Fig. 4A, lower panel) APPswe-PS1ΔE9 mice stained with anti-NeuN antibody demonstrate increased NeuN+ neurons in BMT-recipients. Quantification of total RGCL neurons showed significant preservation with BMT (Fig. 4B) (P<0.05, student's t test). We also quantified RGCL neurons in age-matched control (Fig. 4D, upper panel) and 13-month-old BMT-recipient (Fig. 4D, lower panel) wt mice and, to our surprise, found similar neuroprotective effects in RGCL density (Fig. 4E) (P<0.05, student's t test) as in APPswe-PS1ΔE9 mice. Indeed, RGCL neuron density was not significantly different between untreated APPswe-PS1ΔE9 and wt mice at 13 months of age.


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)

BMT mediates neuroprotection of RGCL neurons in APPswe-PS1ΔE9 and wt mice.A–C: RGCL neurons were identified using anti-NeuN antibody and visualized with Cy3-conjugated secondary antibody in 13-month-old APPswe-PS1ΔE9 and wt mice. Representative photomicrographs of NeuN+ RGCL neurons in control (A, top) and BMT-recipient (A, bottom) APPswe-PS1ΔE9 mice demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (B) and inner retinal (NFL+RGCL+IPL) thickness (C). D–E: Representative photomicrographs of NeuN+ RGCL neurons in 13-month-old control (D, top) and BMT-recipient (D, bottom) wt mice also demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (E). F: No effects on retinal thickness in wt recipients compared with the wt controls. *P<0.05, n = 6–10, student's t test. Scale bar  = 50 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672108&req=5

pone-0064246-g004: BMT mediates neuroprotection of RGCL neurons in APPswe-PS1ΔE9 and wt mice.A–C: RGCL neurons were identified using anti-NeuN antibody and visualized with Cy3-conjugated secondary antibody in 13-month-old APPswe-PS1ΔE9 and wt mice. Representative photomicrographs of NeuN+ RGCL neurons in control (A, top) and BMT-recipient (A, bottom) APPswe-PS1ΔE9 mice demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (B) and inner retinal (NFL+RGCL+IPL) thickness (C). D–E: Representative photomicrographs of NeuN+ RGCL neurons in 13-month-old control (D, top) and BMT-recipient (D, bottom) wt mice also demonstrate neuroprotective effects of BMT through preservation of RGCL neurons (E). F: No effects on retinal thickness in wt recipients compared with the wt controls. *P<0.05, n = 6–10, student's t test. Scale bar  = 50 μm.
Mentions: Retinal neuronal degeneration is associated with Aβ deposition in AD [47], [48] and loss of retinal neurons in GCL has been demonstrated in both clinical and experimental AD [9], [49]. We hypothesized that BMT-mediated Aβ reduction would result in neuroprotection in retina, so we evaluated RGCL neuron survival in non-transplanted and BMT recipient APPswe-PS1ΔE9 mice using immunofluorescence. Representative photomicrographs of RGCL of age-matched control (Fig. 4A, upper panel) and 13-month-old BMT-recipient (Fig. 4A, lower panel) APPswe-PS1ΔE9 mice stained with anti-NeuN antibody demonstrate increased NeuN+ neurons in BMT-recipients. Quantification of total RGCL neurons showed significant preservation with BMT (Fig. 4B) (P<0.05, student's t test). We also quantified RGCL neurons in age-matched control (Fig. 4D, upper panel) and 13-month-old BMT-recipient (Fig. 4D, lower panel) wt mice and, to our surprise, found similar neuroprotective effects in RGCL density (Fig. 4E) (P<0.05, student's t test) as in APPswe-PS1ΔE9 mice. Indeed, RGCL neuron density was not significantly different between untreated APPswe-PS1ΔE9 and wt mice at 13 months of age.

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