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.
Highlights
Advanced age represents the strongest risk factor for Alzheimer’s disease (AD) but is associated with degenerative changes of brain and retina in the absence of clinical disease
In agreement with previously published observations, microglia in APPswe-PS1DE9 mice were identified in outer plexiform layer in addition to layers of inner retina normally populated with microglia [22]
bone marrow transplantation (BMT) led to reduced retinal Amyloid b (Ab) and paired helical filament (PHF)-tau and normalized total microglia, the pathologic effects of AD on retinal ganglion cell layer (RGCL) neuron survival were small compared with the effects of normal aging
Summary
Advanced age represents the strongest risk factor for Alzheimer’s disease (AD) but is associated with degenerative changes of brain and retina in the absence of clinical disease. Microglia are the primary innate immune effector cells in the central nervous system (CNS), and respond to toxic stimuli via multiple functions, including migration to the insult, phagocytosis of toxic molecules or debris, and elaboration of immunomodulatory molecules, such as cytokines and chemokines, as well as directly neurotoxic reactive oxygen species (ROS) [25,26]. Microglia can be both beneficial and harmful, depending on the balance between neuroprotective and cytotoxic functions [27,28,29], but innate immune activation is altered in chronic neurodegenerative conditions to promote exaggerated microglial responses and a predominance of neurotoxic proinflammatory and oxidative microglial activity [30]. An important therapeutic challenge is balancing deleterious and beneficial aspects of microglial activation to promote a neuroprotective phenotype
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