Alzheimer's disease (AD) is a devastating neurodegenerative disease that is, according to the National Institute on Aging, the most common form of dementia among older people. (1) Dementia is characterized by impairment in many mental faculties including, but not limited to: language, memory and perception. (2) Neuroinflammation is known, at this point in time, to play a role in AD. What exactly inflammation has to do with AD is currently a topic of much debate in scientific circles. An analysis of microarray data using microarray techniques identified 5 cytokines (immune system signals) to be important biomarkers of AD. (3) One of the cytokines identified in that study is IL-1, the production of which has been identified to be critical to the formation of the filamentous protein tangles that are a hallmark of AD. (4) This led a team of researchers at the University of California, Irvine to attempt inhibition of IL-1 signaling in a mouse model of AD with the application of an antibody directed against IL-1R (the receptor for IL-1) with the hope of improving AD symptoms. (5) This study is the focus of this blog post.
The researchers first did a behavioral study to test the efficacy of the antibody treatment on the cognitive abilities of their murine subjects. These mice are not your average laboratory mice; they have had three genes introduced into their cells that result in the accumulation of protein deposits and neuronal miscommunication that plague AD patients. (6) After treatment with the anit-IL-1R antibody, mice showed considerable improvement over non-treated mice in terms of their ability to navigate a water maze and to recall traumatic events (see figure below).
These data suggest that treatment of these 3xTg-AD mice, as they are called, with anti-IL-1R antibodies successfully rescues at least some of the cognitive defects associated with AD, namely defects in memory and perception.
The researchers did not merely call this a triumph over AD and declare that they had found a cure. They were curious to see what effect treatment with anti-IL-1R antibodies had on the 3xTg-AD mice at the cellular level. In order to do this, the researchers quantified the numbers of protein deposits detected by immunostaining in the brains of mice that either received the antibody or received nothing at all. They found a significant reduction in the overall levels of protein deposits, but no difference in the intensity or density of the deposits that did form (see figure below).
These data suggest that treatment with anti-IL-1R antibodies can halt the progression of AD, but cannot reverse the course of the disease.
The researchers then decided to further characterize the effect of anti-IL-1R antibody treatment at the molecular level to better understand the mechanism of treatment which might lend insight into the overall disease causing mechanism of AD itself. This was accomplished by western blotting, which is a technique used to determine levels of proteins relative to one another, of intracellular signaling proteins that are known to be involved in immune cell communication. It is important to note that these experiments were performed on cultured human neurons that either received anti-IL-1R antibodies, IL-1, or the IL-1R antibody and IL-1. This switch of models was done in order to move towards a validation of this treatment paradigm in humans. The researchers found significant changes in the concentration of β-catenin, phospho-GSK-3β and phosphor-Akt that signify a return to normal neuronal activity in the neurons that received anti-IL-1R antibodies (see figure below).
These data primarily suggest that the progression of AD is mediated by a reduction of Wnt/β-catenin signaling, which all of the abovementioned signaling proteins are components of. These data also suggest that treatment with anti-IL-1R antibodies may be an effective therapeutic paradigm in patients with early onset AD, as this treatment regimen merely halts the progression of AD but does not reverse its effects.
This research has identified an exciting new target for therapeutic agents in the treatment of AD, IL-1R. Unfortunately, these results are only applicable to 3xTg-AD mice and cultured human neurons, both of which serve as good disease models but are far from the actual disease state of AD. Therefore, further trials, perhaps in simian models of AD, or even in pre-clinical settings may be warranted before use as a therapeutic agent. Other inhibition methods of IL-1 signaling may be attempted as well which could include small molecule inhibitors or RNA interference. The march of research inexorably moves forward towards a cure, with the contributions of hardworking scientists like the ones who performed this research.
3) Gómez Ravetti, M., & Moscato, P. (2008). Identification of a 5-protein biomarker molecular signature for predicting Alzheimer’s disease. PloS one, 3(9), e3111.
4) Li, Y., Liu, L., Barger, S. W., & Griffin, W. S. T. (2003). Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience, 23(5), 1605-11.
5) Kitazawa, M., Cheng, D., Tsukamoto, M. R., Koike, M. A., Wes, P. D., Vasilevko, V., Cribbs, D. H., et al. (2011). Blocking IL-1 Signaling Rescues Cognition, Attenuates Tau Pathology, and Restores Neuronal β-Catenin Pathway Function in an Alzheimer’s Disease Model. Journal of immunology (Baltimore, Md. : 1950).
6) Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., et al. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron, 39(3), 409-21.