Today at the annual meeting of the Society for Neuroscience, Lee Goldstein of Massachusetts General Hospital presented evidence suggesting that the Aβ peptide occurs in the eyes of people with Alzheimer’s disease, raising the intriguing, if distant, prospect that this finding could possibly be developed into a biomarker or diagnostic test. The work is in its early stages and has not been independently reproduced.
Using a number of different antibodies, Goldstein et al. claimed to have detected Aβ in human lens tissue at levels similar to those found in brain and CSF. The scientists obtained postmortem lenses from 10 people with pathologically confirmed Alzheimer’s and reported that they found Aβ in all of them, but not in control lenses from healthy people, or people with other neurodegenerative diseases. The AD cases had Aβ levels four times higher than the controls, Goldstein said.
Goldstein cited several lines of evidence, including biochemistry and electronmicroscopic immunogold labeling of the lenses, that suggest this Aβ might occur in the cytoplasm of the lens. That would make this study the first to demonstrate cytoplasmic Aβ. Generated from APP by cleavage in a membrane compartment, Aβ has indeed been detected intracellularly (learn more about this during our upcoming Alzforum Live Discussion on intracellular Aβ with Gunnar Gouras), but to date, intracellular Aβ always appeared to be in a membranous organelle.
In studying the AD lenses, Goldstein, who works with Ashley Bush and others at MGH, discovered that the people with AD had had a form of cataract, whose incidence and prevalence rates are unknown. (Incidentally, Goldstein added, people with Down’s syndrome not only develop Alzheimer’s pathology, they almost always also develop cataracts.) A leading form of age-related blindness, cataracts come in many different forms. The one at play here, called a supranuclear cataract, is unusual in that the deposits form on the back of the lens and are not visible with the naked eye. People with this type of cataract see normally and, therefore, do not see a doctor about it, leading Goldstein to suspect that this form of cataract may frequently go undetected, even though it can be seen with the split lamps used in eye exams.
The affected cells are also unusual in that they have lost most organelles. They are largely empty sacks of cytoplasm, presumably to enable light to pass through the lens without diffraction, Goldstein said. The investigators do not know how early in the disease this change occurs. All patients studied to date had advanced Alzheimer’s. To find out, they are collaborating with Marilyn Albert and others at MGH who are following with repeated imaging tests a cohort of people to learn which measurements will enable them to predict who will convert to Alzheimer’s disease among those with mild cognitive problems.
Goldstein presented experimental data to bolster his finding, including SELDI-mass spectrometry analysis of Aβ extracted from the lens of a woman with AD, Western blots used with different sets of Aβ-antibodies, Congo Red labeling of lens tissue, and in vitro studies showing that the lens Aβ binds specifically with other cytosolic proteins, for example, the chaperone alpha-B crystalline. Other in-vitro studies indicated that lens Aβ aggregates into protofibrils in a metal-dependent oxidative mechanism, and that metal chelators can inhibit this process. The human lens contains many types of misfolded, aggregating protein. —Gabrielle Strobel.
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