A Deadly Dance
What mice can tell us about the connection between Alzheimer’s and immune function
One of the consequences of aging is a deteriorating immune system. As we get older, our ability to mount robust or functional immune responses fades leaving us more vulnerable than ever to the force of disease.
One of the key hallmarks in Alzheimer’s disease (AD) is the accumulation of toxic amyloid protein in the brain, which can be seen as amyloid plaques both in human patients and in many AD animal models. By looking carefully, brain samples from human AD patients and animal models cells of the immune system (both peripheral and resident inflammatory cells) as well as many related inflammatory factors are found around the amyloid plaques.
It is has been suggested that accumulation of the inflammatory cells around the plaques is a result of immune cells trying to scavenge the detrimental and toxic amyloid to protect the brain neuronal tissue. However, as the disease progresses with aging these immune cells not only lose their ability to clear away these toxic proteins, they apparently release increasing amounts of inflammatory factors that cause further inflammation and damage to the brain. A growing number of immune-related genetic variants also appear to increase susceptibility to late-onset Alzheimer’s disease.
Deciphering the mechanisms driving this primarily protective, but in disease self-destructive behavior could potentially lead to therapies that might reverse the course of a devastating condition afflicting more than 36 million people worldwide. Yet the dozens of preclinical mouse models that researchers now use to assess different behavioral deficits and pathological hallmarks of Alzheimer’s have not translated well into human disease, in part because the immune systems of mice and men are different. This is particularly true when it comes to the innate immune system, as has been demonstrated by Duke University neuroscientist Carol Colton and others.
Colton, a panelist at last week’s Society for Neuroscience luncheon session sponsored by Charles River Laboratories, was among the first scientists to demonstrate that microglia are a macrophage—a type of immune cell—that scavenge the central nervous system (CNS) for plaque and respond to injury by killing invading organisms. Colton’s group has evaluated the inflammatory mechanism and its role in animal models of Alzheimer’s disease and have found that many of the mouse models commonly used in Alzheimer’s studies expresses an enzyme called nitric oxide synthase 2 (NOS2), which is not found to the same extent in humans. NOS2 produces nitric oxide (NO), a highly-reactive oxidant that helps microglial cells of the brain gobble up errant cells. NO is also involved with regulation of inflammatory processes, which makes it an interesting factor from the disease mechanism point of view.
The striking differences in NOS2 levels make it difficult to recapitulate human disease in many of these AD mouse models. However, a relatively novel transgenic model, known as the CVN mouse, has proven to be more than satisfactory in this respect. Developers of this mouse crossed a mouse commonly known as APPSwDI transgenic mouse with mNOS2- knock out mouse, which resulted in a new and unique model for Alzheimer’s research that can be used for basic and applied neuroscience. Colton’s group has found that these CVN transgenic mice recapitulated many of the features of Alzheimer’s disease, such as a neuronal cell death, and a rise in phosphorylated tau protein and accumulation of amyloid plaques in the brain. Also observed in these mice were progressive memory loss with age, and increases in immune system activation and inflammation.
Tracking Disease Progression
By using the CVN mouse model, scientists at Charles River are currently applying biomarker tools, such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), to evaluate anatomical and metabolic changes in the brain during disease progression. These noninvasive research tools also enable the evaluation of efficacy of novel therapeutics at the metabolic and anatomical level in the brain.
Importantly, MRS changes seen in the hippocampus of the CVN mice are similar to those previously reported from AD patients, which highlights the translational potential of this method and builds an important bridge between animal models and human disease. In addition to the fact that MRS changes in CVN mice appear similarly as in human AD, they also correlate with the animal’s progressive memory impairments. This suggests that changes, such as decreased concentrations of a metabolite called N-acetyl aspartate (NAA)—a marker of viable neurons—can be used as a surrogate marker for neuronal survival in the hippocampus. Moreover, MRI/MRS tools can be used multiple times for chronic monitoring of brain anatomical and metabolic profiling during a single experiment.
Will the CVN model or others like it help find new therapies to counter AD? While multiple compounds have demonstrated efficacy in CVN mouse model studies at Charles River, it’s far too soon to tell whether any of these therapies will work in people after clinical trials. However, the CVN mouse model brings to the field an exciting, state-of-the-art disease model with all the major hallmarks of the human Alzheimer’s disease. This could potentially speed up the development of novel effective therapies for this devastating Alzheimer’s disease.
What is clear, and what the Society for Neuroscience meeting emphasized, is that there are no magic bullets. As illustrated in a recent Eureka blog post, scientists will need multiple research models and tools to piece together the puzzle of this strange disease.