Alzheimer's disease is an infamous and debilitating neurological disorder that causes profound memory loss. A major physical characteristic of the disease is the buildup of amyloid-β plaques in the brains of afflicted patients. Scientists have constructed antibodies that can specifically target and attack these plaques in diseased brains, and application of these antibodies results in decreased presence of amyloid-β plaques in humans; however, these treatments often still fail to confer cognitive benefits to patients.

A recent study by Busche et al. (Nat. Neurosci. 18, 1725–1727; 2015) examined this conundrum in a mouse model of Alzheimer's disease. The authors used transgenic mice that overexpress a mutated human amyloid precursor protein, producing higher concentrations of amyloid-β in the neocortex. The researchers then applied the monoclonal antibody 3D6, which was developed to attack amyloid-β plaques. 3D6 is the mouse equivalent of bapineuzumab, a humanized antibody that has been unsuccessfully employed to treat human Alzheimer's patients.

The authors confirmed that the immunotherapy did result in decreased presence of amyloid-β plaques. However, using two-photon calcium imaging in these treated mice, the researchers discovered significant neurophysiological problems. They found that a large proportion of neurons had hyperactive calcium signals, and in nearly half of the treated mice, the researchers also found an unusually large amount of neuronal synchrony. Such synchrony is characteristic of seizures, and this could help promote the onset of epilepsy that is seen in many mouse models of Alzheimer's disease. Importantly, when the 3D6 antibody was administered to wild type mice, the animals did not display this hyperactivity in calcium signals. Therefore, these neurophysiological symptoms likely result from a combination of mice overexpressing the amyloid precursor protein and the application of the 3D6 antibody.

The discovery that amyloid-β plaques can be reduced via passive immunotherapy with antibodies like bapineuzumab has led to much excitement about a potential cure for Alzheimer's disease. However, the discovery that these antibodies do not ameliorate the symptoms of patients has been disheartening. The study by Busche et al. provides important insight for treatments of Alzheimer's disease, and shows that the process of repairing brain dysfunction is complicated, often resulting in unintended consequences. Studies such as this are key to gaining a better understanding of Alzheimer's disease and will lead to more focused efforts to develop therapies that combat both the anatomical and neurophysiological symptoms of the disorder.