The search for ways to prevent or treat Alzheimer's disease has been stymied in part by difficulties in reliably delivering therapeutics into the brain to prevent proteins there from depositing fibrous plaques that damage synapses and ultimately wreck one's cognitive abilities. Researchers have experimented with antibodies, peptides and even nanoparticles to find some way of effectively preventing plaque formation but these efforts have yet to yield an anti-Alzheimer's drug.
Now, two papers by researchers at pharmaceuticals giant Genentech, based in South San Francisco, Calif., describe the development of a new antibody that has shown promise in animal studies by blocking the beta-secretase 1 (BACE1) enzyme that contributes to the buildup of Alzheimer's-inducing brain plaque. The results are detailed in the May 25 issue of Science Translational Medicine.
Antibodies have proved to have two major weaknesses in fighting Alzheimer's—they have difficulty penetrating the blood–brain barrier and then, even if successful there, they fail to reach their protein targets. Genentech's work provides a proof-of-principle that both of these limitations potentially can be overcome, Steven Paul, a Cornell University Weill Medical College professor of neuroscience and psychiatry, wrote in a commentary in the same journal accompanying the research.
Endothelial cells in the blood-brain barrier protect the brain from potentially harmful chemicals and typically have prevented the passage of drugs in strong enough concentrations to inhibit BACE1 activity, which produces small proteins called amyloid-beta peptides that aggregate in the brains of Alzheimer's patients. "Amyloid deposits in the brain are believed to precede and somehow trigger the neurodegeneration and loss of synapses that causes Alzheimer's," adds Paul, who is also the director of Cornell's Appel Alzheimer's Disease Research Institute.
The Genentech researchers' strategy for increasing antibody uptake in the brain was to create an antibody that would bind to a receptor called transferrin that could ferry it across the blood-brain barrier and then get free of the receptor upon reaching the brain, where it would then bind with BACE1. Genentech reports that mice and primate subjects given doses of the antibody experienced a sustained reduction in amyloid-beta peptide concentrations in their bloodstreams and a "modest" reduction of peptide levels in the brain. The former indicates success in disrupting BACE1's work, while the latter provides some evidence that the antibodies made it to the brain.
Genentech's team is now focusing on improvements that would increase the brain uptake and potency of their antibody.
Some researchers have turned their attention to nanotechnology in an effort to find some way of slowing the accumulation of amyloid-beta peptides. Nanoparticles in theory can penetrate the blood-brain barrier and target BACE1 better than antibodies but finding nontoxic substances has proven difficult. A multidisciplinary team of scientists from the University of Michigan at Ann Arbor and South Korea's Kyungpook National University recently reported in Angewandte Chemie International Edition having resolved at least some of nanotech's shortcomings by using cadmium telluride (CdTe) nanoparticles with a tetrahedral shape and negative charge to interfere with amyloid-beta peptide formation. Still, CdTe is not biocompatible and this experiment could not serve as anything more than an example of how certain nanoparticle shapes might someday inspire an effective anti-Alzheimer's treatment.
Image courtesy of Julien Tromeur, via iStockPhoto.com