Possible reasons found for Alzheimer’s treatment failure

Agglutinated proteins in the brain, known as amyloid-β plaques, are a key characteristic of Alzheimer’s. One treatment option uses special antibodies to break down these plaques.

This approach yielded good results in the animal model, but for reasons that are not yet clear, it has so far been unsuccessful in patient studies.

Scientists at the Technical University of Munich (TUM) have now discovered one possible cause: they noticed that, in mice that received one antibody treatment, nerve cell disorders did not improve and were even exacerbated.

Immunotherapies with antibodies that target amyloid-β were long considered promising for treating Alzheimer’s. Experiments with animals showed that they reduced plaques and reversed memory loss. In clinical studies on patients, however, it has not yet been possible to confirm these results.

A team of researchers working with Dr. Marc Aurel Busche, a scientist at the TUM hospital Klinikum rechts der Isar Klinik und Poliklinik für Psychiatrie und Psychotherapie and at the TUM Institute of Neuroscience, and Prof.

Arthur Konnerth from the Institute of Neuroscience has now clarified one possible reason for this. The findings were published in Nature Neuroscience.

Immunotherapy Increases Number of Hyperactive Nerve Cells

The researchers used Alzheimer’s mice models for their study. These animals carry a transgene for the amyloid-β precursor protein, which, as in humans, leads to the formation of amyloid-β plaques in the brain and causes memory disorders.

The scientists treated the animals with immunotherapy antibodies and then analyzed nerve cell activity using high-resolution two-photon microscopy. They found that, while the plaques disappeared, the number of abnormally hyperactive neurons rose sharply.

Hyperactive neurons can no longer perform their normal functions and, after some time, wear themselves out. They then fall silent and, later, possibly die off,”

“This could explain why patients who received the immunotherapy experienced no real improvement in their condition despite the decrease in plaques.”

Dr. Marc Aurel Busche.

Released Oligomers Potential Reason for Hyperactivity

Even in young Alzheimer’s mice, when no plaques were yet detectable in the brain, the antibody treatment led to increased development of hyperactive nerve cells. “Looking at these findings, even using the examined immunotherapies at an early stage, before the plaques appear, would offer little chance of success. As the scientist explains, the treatment already exhibits these side effects here, too.

“We suspect that the mechanism is as follows: The antibodies used in treatment release increasing numbers of soluble oligomers. These are precursors of the plaques and have been considered problematic for some time now. This could cause the increase in hyperactivity,” says Busche.