Antibody Fragment Fights Alzheimer's in Mice
Mice models of Alzheimer's have been treated successfully with an antibody fragment designed by UAB researchers from the Department of Biochemistry and Molecular Biology. One abdominal injection and only five days later the animals improved their memory and ability to learn as the result of less aggregated toxins and an increase in the number of neurons. The research was published in three articles in the latest edition of the mAbs journal.
Researchers at the Biosciences Unit of the Department of Biochemistry and Molecular Biology, in collaboration with the UAB Institute of Neuroscience (INc), have conducted trials with mice by injecting a specific antibody fragment against soluble aggregates of the A peptide, responsible for the toxicity and cell death characteristic of Alzheimer's disease. The beneficial effects were seen at behavioral, cellular and molecular levels five days after an intraperitoneal dose was administered.
Since the first case of Alzheimer's was described, the disease has been associated with the presence of insoluble deposits called amyloid plaques. However, in the past decade researchers have been able to conclude that the neuronal death characteristic of the disease is not due to the presence of these plaques but to the toxicity of the soluble aggregates preceding them (and called oligomers), formed by the A peptide.
Immunotherapy, consisting of the use of antibodies as a treatment for the disease, is turning out to be an encouraging tool in the treatment of certain types of cancer and has also been used in trials to treat Alzheimer's disease. Nevertheless, the clinical trial which had advanced most in treating Alzheimer's through passive vaccination - using the bapineuzumab antibody - was halted in 2012 during its last trial phase due to the adverse effects of the treatment. Many scientists believe the effects were the result of administering complete antibodies, which produce inflammation in the brain. For this reason, they propose to administer antibody fragments, which has been seen to be much safer.
The research group directed by Dr. Sandra Villegas, from the Biosciences Unit of the Department of Biochemistry and Molecular Biology of the UAB, thus designed a recombinant antibody fragment (called scFv-h3D6: single-chain variable Fragment), a derivative of bapineuzumab, which only contains the active part that fights against the etiological agent of the disease: the domains of the antibody responsible for the union of Aβ oligomers. Scientists observed how, in human cell cultures, this antibody fragment protects from cell death and described the molecular mechanism by which this antibody fragment removes the Aβ oligomers that cause the disease.
In the latest edition of the mAbs (monoclonal antibodies), a journal specializing in immunotherapy, the research group published three articles which demonstrate the benefits of the treatment using the antibody fragment scFv-h3D6 in mice, and have redesigned the molecule to make it even more efficient.
The mice come from the 3xTg-AD colony, animal models of Alzheimer's disease, provided by Dr. Lydia Giménez-Llort of the UAB Institute of Neurosciences (INCs). Researchers observed how only one injection into the abdomen of the animal and in only five days, the mice improved in memory and learning abilities, as well as having decreased their levels of anxiety.
At molecular level, researchers demonstrated two important facts: first, the new treatment eliminates from the cerebral cortex the A peptide oligomers, the elements causing the disease; and second, that this elimination is linked to the recovery in levels of certain apolipoproteins which are suspected to be the natural eliminators of Aβ peptide aggregations. The study on these apolipoproteins was conducted in collaboration with Dr. Jose L. Sánchez-Quesada, from the Research Institute of the Sant Pau Hospital.
The results of the studies at cellular level were also very encouraging. In addition to demonstrating that in young mice with the disease neuronal death occurs even in the cerebellum, UAB scientists observed how the antibody fragment protected the neurons, either fully in the least affected areas or partially in the highly affected areas.
With the objective of improving the molecule, especially in regard to how long it remains in the blood stream, the UAB group redesigned the molecule based on a molecular model developed in collaboration with Dr. Baldo Oliva from UPF-IMIM. The mutations introduced increase thermodynamic stability by 25 percent and decrease the tendency to aggregate to some 4 Celsius, traits which clearly increase the therapeutic power of the scFv-h3D6 fragment to treat Alzheimer's disease. Not only that, but the redesign scientists published also can be useful for other antibody fragments being produced in other laboratories with the aim of finding effective treatments for different diseases.