New Target Emerges in Search for Alzheimer’s Treatment

Several recent clinical trials involving compounds designed to reduce amyloid plaques in the brain—the hallmark of Alzheimer’s disease (AD)—have failed to counter the illness. Thus, to successfully treat Alzheimer’s, it might be necessary to target other factors contributing to the disease as well.

Three possible candidates are cholesterol, which is a risk factor for AD, as well as IgG antibodies and receptors for IgG antibodies, researchers reported in the September Brain.

The lead scientist was Paula Fernandez-Vizarra, Ph.D., of Germany’s Max Planck Institute of Psychiatry.

She and her colleagues studied mice genetically engineered to have high blood levels of cholesterol. These mice also displayed several neuropathological hallmarks of AD—high levels of amyloid precursor protein and beta amyloid, abnormal tau hyperphosphorylation, and learning and memory impairments.

The researchers found, in the brains of these mice, heightened levels of IgG antibodies and heightened levels of receptors for IgG antibodies in neurons susceptible to amyloid accumulation. Moreover, they discovered that genetically altering these receptors so that they couldn’t function reduced amyloid deposits and abnormal tau hyperphosphorylation and prevented learning and memory impairments.

They thus believe that IgG antibodies and IgG antibody receptors in the brain may contribute to the development of amyloid accumulation and, in turn, Alzheimer’s in individuals with high blood levels of cholesterol. They also suspect that this might be the case because AD patients are known to produce elevated levels of IgG antibodies against nonbrain antigens and to express receptors for these antibodies in neuronal populations vulnerable to AD.

As a result, the researchers suggested that IgG receptors may constitute “a new potential target for slowing or preventing Alzheimer’s disease” in individuals with high cholesterol levels, especially since simply giving human subjects with high cholesterol levels cholesterol-lowering drugs has not proven effective at countering AD.

The study was funded by the Spanish Ministry of Science, several other Spanish organizations, and the Lilly Foundation.

An abstract of “Immunoglobulin G Fc Receptor Deficiency Prevents Alzheimer-like Pathology and Cognitive Impairment in Mice” is posted at http://brain.oxfordjournals.org/content/135/9/2826.abstract.