In Alzheimer’s disease (AD), two naturally occurring proteins, amyloid-beta and tau, become pathological and form lesions in the brains of patients. The amyloid lesions occur outside the cell, where the sticky protein forms plaques. With tau, the lesions form inside the cells. Under normal conditions, tau helps provide stability for the neuron’s transportation network. In AD, tau stops performing its normal job and becomes aggregated into tangles. How to remove these lesions from the brain of patients has been a major focus of AD research.
One potential method is immunotherapy, or using antibodies which bind to amyloid-beta or tau and promote their clearance. This approach was first used to target the amyloid-beta plaques. Removing the plaques produced improvements in mouse models of AD, and moved forward into human trials. However, the results of the trials were disappointing with the treatments showing limited effectiveness and a small percentage of the participants experienced adverse side effects. Removing amyloid may not be enough to stop the disease when the patient already has symptoms.
These findings shifted the focus on the other pathological protein, tau, which was already being targeted for treatment by several groups. It was initially thought that trying to target tau lesions using antibodies would be a difficult task because, unlike the amyloid plaques, tau tangles are inside neurons. However, it was shown, first by our group and then confirmed by several others, that tau immunotherapies are effective in mouse models and that tau antibodies can enter neurons. Second, several laboratories have shown that tau pathology can spread between cells both in culture and in animals, suggesting that it can be targeted outside the cell. In a recent study by Congdon, Lin, and colleagues in Molecular Neurodegeneration, the researchers explored this issue using two different tau antibodies in animal and cellular models. In mice, one antibody treatment diminished tau pathology and improved memory. Further tests were carried out in cultured neurons using the same antibodies and pathological tau isolated from an Alzheimer’s brain. When the tau was added alone, it caused cell death and an increase in pathology in the remaining cells. They then determined if the antibodies could prevent this and if they worked primarily inside or outside the neuron.
Like in the animals, only one of the antibodies was effective and how it works depends on where the pathological tau was when the antibody was added. In one series of tests, the tau and antibody were added to the cultures at the same time. Under these conditions, the bulk of the tau was outside of the cell and the antibody was able to bind to it and prevent it from being taken up by the neurons and having toxic effects. In another set of experiments, the tau was added 24 hours before the antibody. This incubation allowed the cultured neurons to internalize the tau. When the antibody was added, it also entered the cells, bound to the internalized tau and prevented its toxicity. Under these conditions, the antibody was working inside the neuron. In both cases, the antibody was able to prevent neuronal loss and pathological changes caused by the human tau that was isolated from an Alzheimer’s brain. Further studies showed that the antibody could also reduce the spread of tau pathology between neurons.
Interestingly, only one of the two tau antibodies worked but it was effective in all the assays, which supports their use for screening other tau antibodies. Surprisingly, the antibody that bound better to most forms of tau was ineffective. The effective antibody bound strongly only to a particular soluble form of the Alzheimer’s tau, which clarifies which form of tau is most toxic and how best to target it with antibodies.
Overall, these findings indicate that both external blockage and internal clearance of toxic tau protein, are feasible with antibodies. The importance of each pathway, likely depends on the antibody as some investigators have reported neuronal uptake of tau antibodies whereas others do not see it with their antibodies. Because most of pathological tau protein is found inside neurons, it would make sense that the most effective antibodies would clear tau both inside and outside the cell.
BrightFocus previously funded Dr. Congdon for research regarding tau and Alzheimer's disease.
Dr. Sigurdsson spoke at the the Alzheimer's Fast Track workshop on the topic of “Novel Immunotherapies” in 2014, which was coordinated by BrightFocus.
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