Imaging Alzheimer-Related Pathological Changes: Immune-Mediated, Therapeutics and Toxicities

Lay Summary

Exploring how an Experimental Therapeutic Vaccine for Alzheimer’s Produces Life-Threatening Brain Inflammation

This academic research study will examine how the first experimental therapeutic vaccine, designed to reduce brain accumulation of amyloid in Alzheimer’s disease, caused a life-threatening inflammatory response in some of the patients participating in the initial clinical trial sponsored by the vaccine’s pharmaceutical company developer.  The findings could help guide future development of Alzheimer’s therapies that avoid this serious, and sometimes deadly, inflammatory complication.

Alzheimer’s disease is characterized by accumulation in the brain of the protein called amyloid. A pharmaceutical company recently developed a therapeutic vaccine designed to reduce the build-up of amyloid.  Animal studies indicated that the small amount of amyloid contained in the vaccine stimulated the animals’ immune systems to attack amyloid when they subsequently encountered it in the brain.  Based on the animal testing, the Food and Drug Administration approved a small clinical trial of vaccine in 16 Alzheimer’s patients to determine the vaccine’s relative safety and assess initial indications of its efficacy.  Some vaccine recipients showed evidence of slower rates of cognitive clinical decline compared to untreated patients.

The trial was abruptly halted, however, when five percent of the patients developed life-threatening meningoencephalitis, a devastating inflammation in the brain.  One of these patients died.  An autopsy of this patient’s brain showed decreased amounts of amyloid, compared to the amount usually found at autopsy of Alzheimer’s patients.  This patient’s autopsy also showed evidence that a large number of immune T cells had been activated.

These autopsy findings have prompted Harvard researchers to develop a new mouse model that, when imaged, will help in understanding the interaction between the therapeutic vaccine and the immune T cells’ production of a massive inflammatory response.  While the vaccine is designed to stimulate production of immune T cells to attack the amyloid, it is not clear why the T cells produced the large inflammatory response.  The Harvard researchers’ new animal model will try to help address that question.

The investigators have developed a fluorescent compound to label immune T cells, and the T cells’ actions that occur in Alzheimer’s disease in response to the experimental vaccine now can be viewed using microscopy in a new animal model.  The animal model was produced by breeding a mouse model of Alzheimer’s disease with a strain of mice in which specific subpopulations of immune T cells have been engineered to contain fluorescent proteins.  This resultant new Alzheimer’s disease mouse model has T cells that will fluoresce, providing direct visualization of the animals’ immune T cells in different states of activation.  The imaging also will show the fluoresced interaction between the animals’ immune T cells and the antibodies that are stimulated by the vaccine.  This new model is expected to help determine what went wrong in use of the experimental vaccine.  Eventually, this “fluoresced” animal model of Alzheimer’s disease should be able to be used to study the effects of future experimental therapies that are intended to modify the immune system’s response to immunizations designed to reduce amyloid accumulation.

Significance:  This new animal model that allows visualization of fluorescently labeled immune T cell subpopulations may help to reveal how experimental therapeutic immunization to reduce amyloid deposits in Alzheimer’s produces a deadly T cell inflammatory response.  By understanding this harmful immune response, the results may provide new insights into future development of therapies that avoid this consequence.  The animal model and technique will provide a means of determining the effects on immune T cells of such future experimental therapeutic vaccines.

Abstract

Imaging Alzheimer-Related Pathological Changes: Immune-Mediated, Therapeutics and Toxicities

Immunization against amyloid-β, the peptide that accumulates in senile plaques and in blood vessels in Alzheimer's disease, causes a dramatic immune response that prevents plaque formation and clears accumulated amyloid-β in transgenic mice. In a clinical trial of amyloid-β immunization, 15 of about 300 patients developed meningoencephalitis. Neuropathological investigations of one patient who died during the trial showed promising evidence of clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization. To continue developing therapies based on amyloid-β immunization, these T cell-mediated inflammatory events must be understood.

In this study, we will develop an in vivo multiphoton imaging technique to investigate leukocyte trafficking in the meninges and cortex. We will combine this with current techniques for in vivo imaging of amyloid pathology to study the effects of amyloid-β immunization in mice transgenic for mutant human amyloid precursor protein (APP). Transgenic mice expressing fluorescent proteins in specific subpopulations of T cells will allow direct imaging of T cells in different states of activation. T cells from these mice will be transferred to APP transgenic and crosses of T cell reporter mice, and APP transgenic mice will be bred, allowing imaging of the interaction of T cells in different states of activation with amyloid pathology during immunization. These experiments will also provide a method of testing the effects of possible Alzheimer's therapeutics that modify the T cell response in amyloid-β immunization. In addition to addressing this clinical problem, the technology to monitor T cell trafficking in the cerebral cortex may also benefit the general field of neuroimmunological investigations.