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Show Low-Density Lipoprotein Receptor-Related Protein Is Decreased in Optic Neuropathy of Alzheimer Disease Lloyd M. Cuzzo, BA, Fred N. Ross-Cisneros, BA, Kenneth M. Yee, BS, Michelle Y. Wang, MD, Alfredo A. Sadun, MD, PhD Background: Alzheimer disease (AD) is associated with optic nerve degeneration, yet the underlying pathophysi-ology of this disease and the optic nerve disorder remain poorly understood. Low-density lipoprotein receptor- related protein (LRP) is implicated in the pathogenesis of AD by mediating the transport of amyloid-b (Ab) out of the brain into the systemic circulation. As a key player in the reaction to central nervous system injury, astrocytes associate with LRP in AD. This study investigates the role of LRP and astrocytes in the pathogenesis of AD optic neuropathy. Methods: To investigate the role of LRP and astrocytes in the pathogenesis of AD optic neuropathy, we conducted immunohistochemical studies on postmortem optic nerves in AD patients (n = 11) and age-matched controls (n = 10) to examine the presence of LRP. Quantitative analyses using imaging software were used to document the extent of LRP in neural tissues. Axonal integrity was assessed by performing immunohistochemistry on the subjects' optic nerves with an antibody to neurofilament (NF) protein. Double-immunofluorescence labeling was performed to investigate whether LRP colocalized with astrocytes, expressing glial fibrillary acidic protein. Results: LRP expression was decreased in AD optic nerves compared to that in controls (P , 0.001). LRP immunoreactivity was observed in the microvasculature and perivascularly in close proximity to the astrocytic processes. Colocalization of LRP in the astrocytes of optic nerves was also demonstrated. The presence of optic neuropathy was confirmed in the AD optic nerves by demonstrating greatly reduced immunostaining for NF protein as compared to controls. Conclusions: The reduction of LRP in the AD degenerative optic nerves supports the hypothesis that LRP may play a role in the pathophysiology of AD optic neuropathy. Journal of Neuro-Ophthalmology 2011;31:139-146 doi: 10.1097/WNO.0b013e31821b602c 2011 by North American Neuro-Ophthalmology Society Alzheimer disease (AD) is the leading cause of dementia in the elderly, affecting 5.3 million people in the United States and 40% of people older than 85 years (1,2). AD may also manifest as optic nerve degeneration (3-7). This presents clinically in patients with mild to moderate AD as abnormal visual evoked responses, poor contrast sensitivity, and a reduction of retinal nerve fiber layer on OCT; in severe AD, there may be impaired visual acuity, visual fields, and color vision (4,8-11). Visual complaints in AD are often attributed to impaired cognition and may be overshadowed by higher cortical visual dysfunction, which occurs frequently in AD patients. The major pathological hallmark of AD is the accu-mulation of amyloid-beta protein (Ab), a neurotoxic pep-tide centrally involved in the pathogenesis of AD (12-16). This may be due to faulty clearance of Ab from the central nervous system (CNS) (15,17-24). The blood-brain barrier (BBB), largely maintained by tight junctions between ce-rebrovascular endothelial cells (25), limits the transport of polar solutes, such as Ab. Receptor mediated-transport accounts for most Ab transported across the BBB (17,19,24,26-28). Low-density lipoprotein receptor- related protein (LRP) is the major receptor at the BBB responsible for clearing Ab from the CNS (19,29,30). A decreased amount of LRP is found in the cerebral micro-vasculature in both human AD brains and transgenic AD animal models and is associated with regional accumulation of Ab as compared to controls (23,24,30-32). Section Editors: Jeffrey L. Bennett, MD, PhD Lynn K. Gordon, MD, PhD Department of Ophthalmology (LMC, FNR, KMY, MYW, AAS), Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California; and VMR Institute (KMY), Huntington Beach, California. Supported by the Research to Prevent Blindness Institutional Grant and Medical Student Eye Research Fellowship, National Institute of Aging grant # P50-AG05142, and National Institutes of Health grant EY03040. The authors state that they have no proprietary interest in the products named in this article. Address correspondence to Alfredo A. Sadun, MD, PhD, Department of Ophthalmology, Doheny Eye Institute, USC-Keck School of Medicine, 1450 San Pablo Street, Los Angeles, CA 90089- 0228; E-mail: asadun@usc.edu Cuzzo et al: J Neuro-Ophthalmol 2011; 31: 139-146 139 Basic Science in Neuro-Ophthalmology Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. LRP also exists in a soluble form (sLRP) in plasma and has been shown to bind to 70%-90% of plasma Ab pre-venting its access to the CNS (33,34). In AD individuals, levels of sLRP in plasma are reduced, thereby allowing free Ab in plasma to enter the CNS (29). LRP is also found in astrocytes (35-37). In response to injury, astrocytes undergo both hypertrophy and hyper-plasia displaying prominent fibrous ramifying processes, enhanced immunoreactivity for glial fibrillary acidic protein (GFAP), and increased release of bioactive molecules. LRP is expressed by astrocytes in normal human brains but ex-pression is increased in AD (35,37). Since the optic nerve is part of the CNS, we hypothesized that LRP was decreased in optic nerves of AD patients possibly contributing to Ab accumulation as part of the pathogenesis of AD optic neuropathy. We conducted an immunohistochemical study, first to histologically verify the presence of AD optic neuropathy and second to characterize the presence of LRP and the extent of its association with the microvasculature and astrocytes in AD optic nerves. METHODS Human Autopsy Specimens Postmortem retrobulbar optic nerves were obtained from 11 AD patients (81.0 6 12.0 years) and 10 control subjects (72.8 6 13.9 years). AD tissues were provided by the Alzheimer's Disease Research Center at the University of Southern California, and controls were obtained from the Lions Eye Bank of Oregon. The diagnosis of AD was confirmed clinicopathologically (38-40). Control optic nerves were from subjects with no history of neurodegen-erative disorders. Patient data are summarized in Table 1. Tissue Processing Nerves were immersion fixed in 10% neutral buffered formalin immediately following enucleation of eyes with optic nerves attached. Dissections of the optic nerves into longitudinal profiles 5 mm in length were performed ap-proximately 7-10 mm behind the globe. Tissues were de-hydrated in ethanol and processed for paraffin embedding. The paraffin tissue blocks were cut at 5 mm on a retractable microtome, and the tissue sections were placed on elec-trostatically charged glass microscope slides for immunohistochemistry. Immunohistochemistry: Immunoperoxidase Labeling Tissue sections were deparaffinized and rehydrated, and the antigen retrieval was performed in a 13 citrate buffer, pH 6.2 (BioGenex, San Ramon, CA) within a steamer bath. The bath was microwaved at 480 W for 10 minutes. The sections were rinsed with tris-buffered saline, and endoge-nous peroxidase activity was blocked with 0.3% hydrogen peroxide. Tissue sections were incubated with a monoclonal mouse anti-human LRP primary antibody (EMD Chem-icals, Inc, Gibbstown, NJ) at a dilution of 1:1,000 in a humidity chamber for 1 hour. Negative control sections were incubated in antibody diluent (Dako North America, Inc, Carpinteria, CA) in the absence of primary antibody. Tissue sections were next incubated in a goat anti-mouse secondary antibody conjugated to horseradish peroxidase (Dako) for 30 minutes. The substrate 3,3'-dia-minobenzidine (Dako) was added to produce a brown reaction product (chromagen). All AD and control tissue sections were either counterstained with Mayer's hema-toxylin (Dako) for general nuclear morphology or immunostained for LRP without counterstain for densi-tometry analysis. Finally, the sections were dehydrated in alcohol, cleared in xylene, and coverslipped. The stained nerves were observed on a Zeiss Axioskop light microscope, and the images were captured with a Spot II digital camera. To examine the axonal integrity in both control and AD optic nerve samples, immunoperoxidase staining was per-formed with a monoclonal mouse anti-human neurofila-ment (NF) protein primary antibody (Dako) at a dilution of 1:500 and counterstained with hematoxylin utilizing the methodology above. TABLE 1. Demographic and clinical data of donor optic nerves Case Age (Years) Sex Braak Stage Duration of Disease (Years) Postmortem Interval (Hours) Controls 1 89 F - - 5.0 2 93 M - - 6.5 3 69 F - - 5.5 4 52 M - - 9.8 5 56 F - - 9.3 6 68 M - - 8.1 7 80 M - - 5.4 8 80 M - - 6.3 9 68 F - - 4.1 10 64 F - - 11.0 AD 1 83 M VI 7 13 2 71 M VI 12 13.7 3 82 M V 6 5.8 4 79 F V 9 5 5 87 F V N/A 6 6 86 M V 3 9 7 98 F V N/A 7.5 8 62 M V 3.5 5 9 80 M V N/A 6.8 10 64 F VI N/A 3.5 11 99 F III 7 12.3 Braak system of staging Alzheimer disease (AD) (38). M, male; F, female; N/A, not available. 140 Cuzzo et al: J Neuro-Ophthalmol 2011; 31: 139-146 Basic Science in Neuro-Ophthalmology Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Immunohistochemistry: Double- Immunofluorescence Labeling Tissue sections were deparaffinized, rehydrated, and sub-jected to antigen retrieval as described previously. Sections were washed with phosphate-buffered saline (PBS) and incubated with 1% BSA with 0.1% Triton X-100 in PBS for 15 minutes. Tissues were incubated with a monoclonal mouse anti-human LRP primary antibody (EMD Chem-icals), as used previously for immunoperoxidase staining, at a dilution of 1:1,000 at 37 C for 1 hour in a humidity chamber. Goat anti-mouse secondary antibody conjugated to fluorescein iso-thiocyanate (Dako) was added at a di-lution of 1:20 for 45 minutes. To determine the association of LRP with astrocytes, tissue sections were incubated with a second primary antibody, a polyclonal rabbit anti-human GFAP antibody (Dako) at a dilution of 1:500 at 37 C for 1 hour. A swine anti-rabbit secondary antibody conjugated to tetramethyl rhodamine iso-thiocyanate (Dako) was added at a dilution of 1:60 for 45 minutes. Tissue sections were mounted with Vectashield containing DAPI (4#, 6-diamindino-2-phenylindole) for nuclear staining. Images were captured on a Zeiss LSM 510 confocal microscope. Quantitative and Qualitative Analyses LRP immunolabeling was quantitatively graded by scan-ning slides with a light microscope at a magnification of 31,000. Twenty images were captured from central to peripheral regions of each nerve section in a systematic, linear, nonoverlapping fashion, and analyzed with AnalySIS image software. The average immunopositive area for every slide and average ratio of specific immunolabeled area to total optic nerve area was recorded. Slides immunohistochemically stained for NF were viewed under a light microscope at 3200 and 31,000. The intensity of immunoreactivity for NF staining was evaluated qualitatively, and AD optic nerve slides were compared to controls. RESULTS Immunoperoxidase Localization of LRP in AD and Control Optic Nerves Immunoperoxidase staining demonstrated that LRP was decreased in AD optic nerves, especially within the vascu-lature, as compared to that in controls (Fig. 1). We observed an increased perivascular LRP staining within AD astrocytes in a punctate perinuclear pattern (Fig. 2 B, D). Our quantitative analysis using densitometry showed that total expression of LRP was significantly reduced in the AD group as compared to controls (Figs. 3, 4). The extent of LRP immunolabeling was 121.5 6 13.3 mm2 (mean 6 standard error) in the control optic nerves and 18.9 6 3.5 mm2 in the AD optic nerves (P , 0.0001; Fig. 4). The 95% confidence interval of the mean quantity of LRP immunostaining was 91.4-151.6 mm2 in controls vs 11.2-26.6 mm2 in AD optic nerves (P , 0.0001). Immunoperoxidase Labeling of NF in AD and Control Optic Nerves Immunoperoxidase staining of NF, as a marker of axonal integrity, demonstrated clear degeneration of AD optic nerves compared to control tissues (Fig. 5). This example is representative of the study population. The majority of the AD optic nerves from the Alzheimer Disease Research Center came from patients with severe AD (Braak stage V-VI; Table 1) and were all severely affected as evidenced by greatly decreased NF staining. Double-Immunofluorescence Labeling for LRP and Astrocytes Double-immunfluorescence labeling revealed colocalization of LRP within GFAP-positive astrocytes of optic nerves in both age-matched controls (Fig. 2 A, C) and AD nerves (Fig. 2 B, D) but to a greater degree in the AD tissues. DISCUSSION We demonstrated a decrease in the expression of LRP in AD optic nerves compared to that in the age-matched controls; this corroborates with other studies showing decreased LRP in AD patients (24,30). We presented histochemical evi-dence of AD optic nerve degeneration by showing a large decrease in NF staining, which is interpreted as a large loss of axons. This is consistent with the previous reports identifying optic neuropathy in AD patients (3-7). In humans and animal models, LRP has been shown to be responsible for clearing Ab out of the CNS via transport across the BBB (19,29,30). Reduced LRP has been iden-tified in the cerebral vasculature of AD patients and appears to be associated with the accumulation of Ab in the brain, which is believed to initiate pathogenic cascades seen in AD (17). Furthermore, the accumulation of Ab within cerebral blood vessels in AD, known as cerebral amyloid angiopathy (CAA), is associated with the cognitive decline of this disease. Decreased clearance of Ab across the BBB may contribute to CAA and parenchymal Ab deposits (17). This is supported by studies that have demonstrated that im-pairment in the clearance of CNS beta-amyloid may be fundamental to the pathophysiology of AD (41). These findings suggest that the decreased expression of LRP found in our study could, by reducing the efflux of Ab out of the optic nerve, play an important role in the pathogenesis of AD optic neuropathy. sLRP under normal conditions is the major endogenous Ab chaperone protein in plasma, acting as a peripheral ‘‘sink'' pulling Ab from the brain to the blood, preventing Ab entrance into the CNS and facilitating its clearance in the liver (29,34). However, there is decreased sLRP in AD, Cuzzo et al: J Neuro-Ophthalmol 2011; 31: 139-146 141 Basic Science in Neuro-Ophthalmology Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. most of which may become impaired by oxidation initiated by reactive oxygen species generated by the receptor for advanced glycation end products (RAGE) proinflammatory cascade (17). RAGE receptors in the BBB are responsible for the influx of Ab into the CNS and have been shown to be upregulated in AD optic neuropathy (42). This suggests that the sLRP ‘‘peripheral sink'' for Ab is compromised in AD, leading to elevated free Ab levels in plasma that exacerbate the increased Ab levels in the CNS via RAGE-mediated transport across the BBB (29). We also found a relative increase in LRP staining in AD astrocytes (Fig. 2). While quantification of the increased LRP staining in AD astrocytes was not performed, the example shown in Figure 2 is representative of the nerves FIG. 1. Immunoperoxidase labeling of vasculature within human optic nerves for LRP. Examples of a capillary from a normal age-matched control (A) and an AD (B) patient. Note the increased staining associated with the vessel wall (arrows) and perivascular tissue (arrowheads) of the capillary in control (A) (31,000). FIG. 2. Immunoperoxidase and immunofluorescence labeling of LRP among glial cells in human optic nerves. Com-parisons of LRP staining in glial cells can be seen in age-matched control (A) and AD (B) (see insets for example). B. Note the increased perinuclear staining (arrows) in the AD glial cells. C and D. Images showing double-immunofluorescence labeling of the optic nerves for LRP coupled to fluorescein iso-thiocyanate (green) and GFAP coupled to tetramethyl rhodamine iso-thiocyanate (red) counterstained with DAPI (blue) to label nuclei in control (C) and AD (D). LRP expression was observed in the cytoplasm of the GFAP-positive astrocytes (arrows). LRP expression was also observed in the astrocytes mainly in a perinuclear region (arrowheads). Note the increased glial staining in AD nerve (D), consistent with the immunohistochemistry shown above (B) (A, B: 31,000; C, D: 32,000). 142 Cuzzo et al: J Neuro-Ophthalmol 2011; 31: 139-146 Basic Science in Neuro-Ophthalmology Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. sampled, as supported by other studies (35,43,44). We demonstrated colocalization of LRP within astrocytes in optic nerves, usually in a perinuclear fashion (Fig. 2), which is also supported by previous studies (44). The increased perivascular LRP staining observed in astrocytes in AD nerves likely represents astrocytic foot processes abutting against the vasculature (44). The expression of LRP in re-active astrocytes, coupled with the perinuclear Golgi net-work staining, suggests that these cells were actively manufacturing LRP. LRP production by these reactive as-trocytes may have been a compensatory response for de-creased LRP in the neighboring vasculature. This could also be part of a process of monocyte recruitment to the area of injury, as LRP binds ligands involved in cell migration in response to injury or infection such as C3 and uPA (16,45). Increasing LRP might also restore Ab homeostasis and contribute to the development of neural networks (16,46,47). Astrocytes are normally neuroprotective, functioning to monitor the surrounding tissue environment, supply nu-trients, support BBB functions, and repair by way of gliosis (48). When chronically activated, they release neurotoxic cytokines and activate destructive pathways (49,50). Cel-lular LRP not only clears Ab but also has the potential to produce Ab. LRP can internalize amyloid precursor protein (APP) and deliver it to the endosomal compartment where it can undergo amyloidogenic processing by b-secretase. This is followed by g-secretase action to produce Ab. As a consequence of increased APP internalization, LRP can enhance Ab secretion (31,51). However, LRP has been shown to modulate APP trafficking between the cell surface and the compartments of the endocytic pathway by FIG. 3. Examples of micrograph sampling for densitometry analysis in age-matched control and AD optic nerves. Immunoperoxidase labeling for LRP can be observed in a control (A) and an AD (B) optic nerve. Note corresponding highlighted color for density of the LRP label in control (yellow) (C) and AD (red) (D) optic nerves, as seen in A and B, respectively (31,000). FIG. 4. The comparison of the mean area of density for LRP immunolabeling in control optic nerves (121.5 mm2) was greater than that in AD nerves (18.9 mm2) (P , 0.0001). Cuzzo et al: J Neuro-Ophthalmol 2011; 31: 139-146 143 Basic Science in Neuro-Ophthalmology Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. interacting with APP in the endoplasmic reticulum (ER) (52). By doing so, LRP has been shown to retain APP in the ER, reducing the levels of APP that reach the plasma membrane (53). Thus, LRP is intricately involved with cellular pathways that suppress Ab generation but that can be altered to facilitate production (54). While we were able to show colocalization of LRP within astrocytes, future studies examining LRP immunolabeling with microglial markers and NF protein may further uncover the compli-cated role of LRP in the pathogenesis of AD optic neuropathy. It should be noted that while the AD subjects were slightly older than the controls, this was not statistically significant (P = 0.13). LRP has been shown to decrease with normal aging in rodents, non-human primates, and AD patients, but it has not been shown to decrease with age in normal humans (29). A potential therapeutic approach to AD optic neurop-athy might be to target the interruption of LRP-mediated internalization of APP, a necessary step for LRP-facilitated production of Ab. LRP and APP must form a complex with the adaptor protein FE65 to internalize APP from the plasma membrane in order to process it into Ab (55). Interrupting this process could harness the protective effects of LRP effluxing Ab from the CNS without the downside of producing more Ab. This is supported by studies that suggest that LRP can be protective against AD (56). An-other potential avenue of treatment would be to develop a synthetic sLRP, which could be administered in-travenously that would bind to Ab with high affinity and minimal toxicity. This could shift the Ab transport equi-librium toward the plasma (21). Furthermore, other studies have shown that administering recombinant LRP clusters can effectively sequester plasma Ab in human AD plasma and in AD mice (18). In mice, sequestration resulted in reductions of Ab accumulation in the brain parenchyma and vasculature. This resulted in improvements in memory, learning, and cerebral blood flow responses (57). In conclusion, our findings demonstrate a significantly reduced expression of LRP in AD optic nerves as compared to that in age-matched controls. This result, along with the LRP expression in the AD microvasculature, is concordant with other investigators' work and supports the hypothesis that decreased LRP may play a role in the underlying pathophysiology of AD optic neuropathy by reduced efflux of Ab out of the optic nerve into the systemic circulation. ACKNOWLEDGMENTS The authors express their gratitude to the USC Alzheimer's Disease Research Center and Lions Eye Bank of Oregon for supplying the tissues. 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