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Increase of receptor for advanced glycation end products in axons, glial cells of optic nerves associated with Alzheimer's, research suggests


Immunohistochemical studies have shown that the receptor for advanced glycation end products (RAGE) is elevated in the optic nerves of patients with Alzheimer's disease. Future studies are expected to provide more information about the role of RAGE in Alzheimer's disease and other neurodegenerative diseases and could lead to new therapeutic options if RAGE is determined to be a causative agent.

Key Points

Fort Lauderdale, FL-Immunohistochemical study of the receptor for advanced glycation end products (RAGE) in the optic nerves of individuals with Alzheimer's disease has shown an increased presence of RAGE in the axons and glial cells when compared with optic nerves from healthy control donors. These findings suggest that RAGE is involved in the neurodegenerative process of Alzheimer's and that therapies to counter its pathogenic effects could minimize the symptoms of this and other disorders.

The research also indicates that the expression of RAGE is an age-dependent process but that Alzheimer's results from an overlap of normal aging and pathology, said Michelle Y. Wang, who presented the findings at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). Wang is a medical student working in the neuro-ophthalmology lab of Alfredo A. Sadun, MD, PhD, at the Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles.

Optic neuropathy

Previous studies have suggested that RAGE is a mediator of pathogenesis in Alzheimer's and other neurodegenerative diseases. A multiligand receptor of the immunoglobulin superfamily, RAGE is a progression factor amplifying immune and inflammatory responses. It is expressed at low levels in normal tissues but becomes upregulated at sites where its ligands accumulate.

To better understand the pathology of RAGE, Wang and colleagues in Dr. Sadun's lab conducted a study to characterize the presence of RAGE in optic nerves from patients with Alzheimer's disease and age-matched controls.

She and her colleagues obtained 10 optic nerves from donors in whom Alz-heimer's disease previously had been diagnosed and six age-matched optic nerves from individuals without an Alzheimer's disease diagnosis. The retrobulbar sections were taken 1 to 3 mm from the globe.

The research team performed immunoperoxidase staining followed by quantitative and qualitative analysis as well as immunofluorescence staining. Double staining was performed for RAGE, astrocytes, and oligodendrocytes.

In the qualitative analysis, the grading scale for RAGE immunolabeling in the Alzheimer's group versus the controls was Grade 0: no staining; Grade 1: mild; Grade 2: moderate; Grade 3: Strong. In the control group, two-thirds had Grade 1 staining and one-third had Grade 2. In contrast, the samples from the Alzheimer's group were equally divided between Grades 2 and 3, Wang said.

Results of the quantitative analysis revealed a steady climb in the percentage of RAGE with increasing age in both groups, but the increase was steeper in the optic nerves from the Alzheimer's patients (p = 0.0002).

Because the control group was slightly younger than the Alzheimer's group, however, the researchers conducted a second analysis involving only individuals aged fewer than 80 years. Significantly more RAGE (p = 0.004) was found among the samples from the Alzheimer's patients.

The role of RAGE

More RAGE was found in the optic nerves from younger Alzheimer's patients than in the nerves from older controls, however. This finding suggests that although RAGE plays a role in the development of Alzheimer's, the disease may be caused by a confluence of pathology and normal aging, Wang said.

Immunohistochemistry results showed that RAGE was evident on the myelin of the axons of the optic nerve and was strongly associated with the glial cells in the nerves from the individuals with Alzheimer's disease. Mild to moderate staining was observed in the control samples.

Researchers still are unsure about the role of RAGE upregulation in Alzheimer's disease, Wang said. RAGE upregulation could be causative, such as a compensatory phenomenon or cellular adaptation, or it could be an effect or end-stage consequence.

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