Glaucoma and Alzheimer disease (AD) might share more than being chronic, age-related diseases with devastating neurodegeneration. Some epidemiological evidence reveals that AD patients are almost three times more likely to have glaucoma than controls (Bayer et al., 2002). Now, cellular biology studies demonstrate that amyloid-β (Aβ)-induced apoptosis may be a common feature of both glaucoma and AD.

Francesca Cordeiro, at the University College London, England, and colleagues used a rat model to study the connection between Aβ and apoptosis in retinal ganglion cells (RGCs), which irreversibly die off under glaucoma’s hallmark of raised intraocular pressure. Their in vivo findings, which were published in the August 7 online edition of the PNAS, indicate that Aβ levels increase in the retina following surgically induced chronic ocular hypertension. In particular, the researchers found that Aβ deposition significantly increased in the retinal ganglion cell layer and that Aβ colocalized with apoptotic RGCs.

First author Li Guo and colleagues used a combination of real-time imaging and postmortem analysis to track dying cells in vivo and correlate apoptosis with Aβ. They tagged the commonly used apoptotic marker annexin 5 with a fluorescent dye and used a confocal laser scanning ophthalmoscope to track dying retinal ganglion cells, from which they observed a peak in Aβ deposition in RGCs 12 weeks after ocular hypertension was induced. To investigate whether the Aβ deposition was a cause or effect, the researchers tested whether exogenous Aβ alters RGC apoptosis in vivo. Physiologically relevant doses of 0.55 nmol full-length Aβ1-42 or 12.5 to 50 nmol Aβ25-35 yielded a peak in RGC apoptosis at 72 hours—the longest time point reported in the paper—after dosing. The lower dose of Aβ42 caused more than twice as much apoptosis as 50 nmol Aβ25-35, suggesting the full-length peptide is much more toxic. These dose-dependent effects were observed in the absence of increased intraocular pressure.

The findings add to earlier reports from Stuart McKinnon’s laboratory at the University of Texas Health Science Center at San Antonio (McKinnon is now at Duke University, Durham, North Carolina) that there is robust expression of Aβ in ocular hypertensive retinas compared to control retinas (McKinnon et al., 2002). The work also hints at a different therapeutic strategy for glaucoma treatment, which currently focuses on controlling glutamate receptor activation that has been linked to RGC apoptosis. In that regard, the NMDA antagonist memantine is supposedly failing to live up to expectations in phase 3 clinical trials of glaucoma, note Guo and colleagues.

Accordingly, the researchers investigated if manipulating Aβ might be a viable treatment strategy. They used single and combined therapies—β-secretase inhibition, Congo red, and an Aβ antibody—to reduce Aβ. In their single treatment experiments, “It appears that the main effect of the treatments is to suppress the early peak of RGC apoptosis over the first three weeks,” Guo and coauthors wrote. Using combination treatments, each targeting different points of the Aβ pathway, the researchers observed greater prevention of RGC apoptosis. Three weeks after ocular hypertension was induced, the three-pronged combination treatment had an 84 percent mean reduction of RGC apoptosis compared to 74 percent in the Aβ antibody treatment alone.

The results sing the familiar tune that the most protection occurs with early treatment. That Cordeiro “didn’t see as efficient neuroprotection later in the treatment again points to how Aβ is [part of] an early negative process,” said McKinnon, in an interview with ARF. “Neurons share a lot of similarities and share similar ways that they die,” McKinnon said. Aβ might be part of the apoptotic process in glaucoma, but that does not mean the trigger for glaucoma is AD, he said. The corollary is also true: having glaucoma does not trigger AD. While having AD seems to accelerate glaucoma, McKinnon said evidence shows it does not work the other way around.—Molly McElroy.

Reference:
Guo L, Salt TE, Luong V, Wood N, Cheung W, Maass A, Ferrari G, Russo-Marie F, Sillito AM, Cheetham ME, Moss SE, Fitzke FW, Cordeiro MF. Targeting amyloid-beta in glaucoma treatment. Proceedings of the National Academy of Sciences. 2007 Aug 7. Abstract

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References

Paper Citations

  1. . High occurrence rate of glaucoma among patients with Alzheimer's disease. Eur Neurol. 2002;47(3):165-8. PubMed.
  2. . Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest Ophthalmol Vis Sci. 2002 Apr;43(4):1077-87. PubMed.
  3. . Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13444-13449. PubMed.

Further Reading

Papers

  1. . Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13444-13449. PubMed.

Primary Papers

  1. . Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13444-13449. PubMed.