Suppressed Retinal Degeneration in Aged Wild Type and APPswe/PS1ΔE9 Mice by Bone Marrow Transplantation

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.

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

“…In line with the above findings, numerous studies examining the retinas of sporadic and transgenic animal models of AD have reported Aβ deposits, vascular Aβ, pTau, and paired helical filament-tau (PHF-tau), often in association with RGC degeneration, local inflammation (i.e., microglial activation), and impairments of retinal structure and function (11,39,40,42,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57).…”

“…These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57). Furthermore, several publications, including ours, have reported a positive response to therapy in reducing retinal Aβ plaque burden in transgenic (ADtg) murine models, often reflecting the reaction observed in the respective brains (40,48,51,52,56,60). To visualize retinal Aβ pathology in vivo, we had previously developed a noninvasive retinal amyloid imaging method for rodent ADtg models, using curcumin as a contrast agent (40,51).…”

Ocular and Visual Manifestation of the Alzheimer’s Disease: A Literature Review, Part I: Animal Models and Human Pathology

“…However, retinal plaques were not detected in another model, the non-Tgwt mice. In this model, Yang et al (10) confirmed a twofold increase in microglia, prominent inner retinal Aβ, paired helical filament-tau, and decreased retinal ganglion cell layer neurons. They also showed that bone marrow transplantation has a protective action against retinal degeneration, resulted from alterations in the immune function and oxidative stress.…”

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

“…Among the family of matrix metalloproteinases (MMP), MMP-9 and MMP-8 are important for the migration of microglia during embryogenesis [3]. Expressed MHC class II [41] Highly expressed MHC class II [21] Expressed MHC class II [42] Neurotoxicity Produced pro-inflammatory cytokines [43] Produced pro-inflammatory cytokines [44] Produced pro-inflammatory cytokines (in brain) [45] Increased ROS [16,46] Reduced ROS [16] Reduced ROS (in brain) [47] Produced nitric oxide [48] Expressed the inducible form of nitric oxide synthase (in brain) [49] Produced nitric oxide [42] Phagocytosis Dead photoreceptors and cell debris (dead cells in brain) [50,51] Unclear Dead photoreceptors and cell debris [50] Living stressed photoreceptors (living neurons in brain) [52,53] Unclear Unclear Amyloid deposits clearance Impaired Aβ clearance and facilitated Aβ deposition [16] Increased Aβ clearance [14,16] Increased Aβ clearance [54] Neuroprotection Produced neurotrophic factors [55] Unclear Produced neurotrophic factors [15] Unclear Unclear Produced anti-inflammatory cytokines [56] Vascularization Promoted the formation of CNV (VEGF, PDGFβ, and ICAM) [55] Pathological neovascularization (IL-1β) [44,57] Promoted the formation of CNV [58] Unclear Physiological neovascularization [59] Unclear…”

“…These cells transfer from the bone marrow to the blood, enter the CNS, and generate microglia in special conditions. In many studies, BM-derived microglia have been identified in the CNS of BM chimera mice that received irradiation [14][15][16]. Nevertheless, it is difficult to avouch the necessity of irradiation or BM transplantation for the migration and generation of BM-derived cells.…”