Major Finding: Non–plaque forming fragments of the amyloid beta protein, once thought to be non-neurotoxic, may be more dangerous to the brain than the full-length, plaque-forming amyloid.

Data Source: A series of in vitro studies.

Disclosures: The work was funded by the National Institute of Aging, National Cancer Institute and Alzheimer's Association. None of the authors declared a potential financial conflict.

Small fragments of the beta amyloid peptide, previously thought to be nontoxic to the brain, may actually be part of the root cause of Alzheimer's disease, new research findings suggest.

These small beta amyloid (Abeta) fragments group together to create pores that let toxic calcium enter neurons, causing neurodegeneration and cell death, Ratnesh Lal, Ph.D., and his colleagues reported in the Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. U.S.A. 2010 [doi/10.1073/pnas.0914251107

The findings may offer some insight into the limitations of Alzheimer's drugs targeted to reduce the full-length beta amyloid peptides, Abeta_1-40/42, which form the brain plaques seen in Alzheimer's and are the supposed cause of the disease.

While these drugs do decrease the amount of Abeta_1-40/42, they also increase the amount of the shorter peptides, which may negate any benefit of the drugs and compound the natural progression of Alzheimer's disease, Dr. Lal said in an interview.

“Any positive effect of these drugs may be masked by the negative effect,” of increasing the number of the pore-forming shorter Abeta peptides, said Dr. Lal, professor of Bioengineering and Mechanical Engineering at the University of California, San Diego.

The findings by Dr. Lal and his colleagues, Ruth Nussinov, Ph.D., and Dr. Bruce Kagan, could revolutionize Alzheimer's drug research, said Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic Arizona, Scottsdale. The idea that nonamyloidogenic fragments are themselves neurotoxic preserves a central role for amyloid in Alzheimer's pathophysiology but alters the specifics in ways that could impact future therapeutic development efforts, he said in an interview.

“The amyloid hypothesis has never accounted for the failure of amyloid-clearing immunotherapy to retard the progression of dementia, or for any of the other treatment failures based on the Abeta_1-40/42 model. This may be a reason why. It is potentially so important in my opinion, that it warrants replication as soon as possible in other labs, and if replicated, should serve as a paradigmmodifying piece of work in our understanding of amyloid's role in Alzheimer's pathogenesis.”

Dr. Lal and his colleagues examined the effect of two short fragments of the Abeta peptide: Abeta_9–42 and Abeta_17–42. They found that both fragments can form mobile ion channels on neuronal cell membranes. When the fragments were added to a culture of mouse fibroblasts that were bathed in a calcium solution, the cells readily took up the calcium. Adding zinc to the mixture, however, blocked the influx of calcium, showing that the pore channel can be inactivated.

When the same procedure was performed on human cortical neurons, the investigators observed an association between the dose of Abeta peptide fragments and how long it took for neurodegeneration to become apparent. The fragments formed pores that allowed calcium to enter the cell. At the smallest dose of the two fragments, it took 24 hours for neurodegeneration to become apparent. It was only detectable with atomic force microscopy. At higher doses, the neurodegeneration was visible with light microscopy by 24 hours. At the highest dose, there was a dramatic reduction in neuronal processes within 15 minutes. Cells showed disrupted, leaking membranes and a decreased number of neurites. Again, cells pretreated with zinc seemed to be protected from damage, even at the highest dosage of the fragments.

The model refines the amyloid hypothesis, Dr. Lal said, suggesting that neurodegeneration may be the result of the smaller Abeta fragments of the larger plaque-forming peptides. “You can put those smaller proteins right on top of neurons in culture and replicate all the damages induced by the full-length amyloid proteins,” he said.

“What we are showing is that the smallest nonamyloid-forming peptides might actually be the most important part of the Abeta hypothesis.”

The next research step, he said, will be to identify which of the 10-12 amino acids that comprise each ion pore control its behavior. “What we are doing is to try and change each one of the proteins to see how it affects the behavior of the pore,” he said. “If you can find the one that closes the pore that would be a target for a small molecule drug.”

Because the research was performed completely in vitro, it's too soon to know how–or even whether–the ion pores would affect Alzheimer's disease progression, said Mark A. Smith, Ph.D., an Alzheimer's disease researcher at Case Western University, Cleveland.

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Neurodegeneration may be the result of the smaller Abeta pieces of the larger plaque-forming peptides.

Source DR. LAL

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