Novel Protein May Offer Target for Alzheimer's Vaccine

Megan Brooks

June 21, 2012

June 21, 2012 — A neuronal protein may offer a potential target for immunization against Alzheimer's disease (AD), new research suggests.

According to investigators from the University of Zurich, ankyrin G (ankG) may represent a novel target for AD immunotherapy.

"We showed that a pathological extracellular deposition of the neuronal protein ankG evokes the production of antibodies in patients with AD, which may reduce the level of beta-amyloid and its related neurological disease," Antonella Chadha Santuccione, MD, of the Division of Psychiatry Research, University of Zurich, in Switzerland, told Medscape Medical News.

Dr. Antonella Santuccione

"These findings could be useful in the design of a vaccine against AD. A vaccination protocol based on the use of anti-ankG antibodies could be protective against neurodegeneration," she added.

The study was published online June 12 in Molecular Psychiatry.

Slowing Disease Progression

As part of their experiments, Dr. Santuccione and colleagues tested sera from 31 patients with AD and 33 age-matched healthy control participants. They found ankG antibodies in roughly 55% of AD sera compared with 24% of control sera (P = .01).

"The frequency of ankG immunoreactive sera as well as the ankG expression in frontal cortex was higher in patients with AD as compared with [healthy control participants], indicating that the ankG immunoresponse is specifically linked to the AD neuropathology," the researchers write.

They also report that AD patients who were immunopositive for ankG antibodies displayed "stable or even improved" cognitive function over a period of 2 years, as measured by the Mini-Mental State Examination, when compared with immunonegative AD patients.

"The rate of cognitive decline in AD patients was faster in the absence of ankG-reactive antibodies," they note.

"This suggests that endogenous ankG antibodies can represent a protective mechanism that slows down the progression of the disease. We are now enlarging the study population to screen for anti-ankG antibodies," said Dr. Santuccione

The researchers also found that neuronal expression of ankG was higher in the AD brain and was redistributed from intraneuronal compartments to extracellular beta-amyloid plaques.

"Further experiments showed that ankG is likely released through exosomes, which are involved in intercellular communication and immune system modulation," Dr. Santuccione explained.

In a mouse model of AD, active immunization with ankG reduced brain beta-amyloid pathology, increased brain levels of soluble amyloid-beta 42, and improved dendritic spine structure.

"Very Novel" Study

Reached for comment on the research, Li Gan, PhD, an investigator who specializes in AD at the Gladstone Institutes, in San Francisco, California, described the study as "interesting and very novel."

"I haven't seen anything like this before. It has good potential, but it's hard to draw conclusions right now, from what they have shown," Dr. Gan told Medscape Medical News.

Dr. Santuccione and colleagues are also studying how ankG can influence the subcellular mechanism leading to AD, and they are further analyzing the potential use of anti-ankG antibodies in human vaccine against AD.

In their article, they point out that ANK3, the gene encoding AnkG, is 1 of the 23 functional candidate genes associated with late-onset AD. ANK3 has also been associated with bipolar disorder, but immunogenicity of ankG in this condition has not been investigated. "It is likely that the presence of anti-ankG antibodies may also influence the clinical course of bipolar disorder. Further studies addressing this possibility in this cerebral condition are required," the researchers write.

A patent application that includes data from this study was filed by the University of Zurich with Dr. Santuccione and 4 other authors listed as inventors. Dr. Santuccione was supported by the Novartis Foundation. A complete list of funding agencies for individual authors is listed with the original article. Dr. Gan has disclosed no relevant financial relationships.

Mol Psychiatry. Published online June 12, 2012. Abstract

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