What’s Old is New
Rather than cause Alzheimer’s Disease (AD) symptoms intentionally in an animal model–like in the case of a transgenic animal–a new research model, developed by our scientists at Discovery Research Services, simply allows rats to grow old and age into their ‘twilight years’ (approximately 20 months). Like most animals do in older age, these elderly rats decline cognitively and ultimately develop Alzheimer’s symptoms as a result of the natural aging process. Compared to research models which focus on only one aspect of AD in young, healthy animals, these aged rats may yield more representative data and thus be more translatable to humans.

The Growing Alzheimer’s Problem
According to a 2011 report from the Alzheimer’s Association, 1 in 8 people aged 65 and older has Alzheimer’s1. As the baby boomer generation continues to age and life-extending medical breakthroughs and advances in technology are developed, the number of disease cases is predicted to rise dramatically. In fact, the Alzheimer’s Drug Discovery Foundation (ADDF) predicts that by the age of 80, 1 in 3 will be affected by the disease. And by 2025, the number afflicted will reach 34 million2.

To date, over 300 investigations have shown to improve the characteristics of AD in research models3. In addition to over 100 years of research however, such studies have yielded only a few drug FDA-approved therapies. On top of this, these drugs, like your average cold medicines–which treat coughs, stuffy noses and headaches–target only the symptoms of disease, not the underlying causes.

Pick a Model, Any Model
In the study of disease, unlocking the mystery in humans requires modeling it in research animals first. Because our biology and genetics have fundamental similarities, what happens in these animals generally reflects what happens in humans. Such is the premise for preclinical trials. But alas, Alzheimer’s is a complex disease. Studying it effectively requires many studies, investigating multiple angles, though a variety of animal models.

Because no one research animal can model all aspects of AD, many exist–each of which mimics different characteristics of the disease. Models may target different biochemical pathways, genetic mechanisms, or functional proteins, and its rate that one animal can model every feature of a disease.

The most commonly used models of Alzheimer’s are transgenic animals that overexpress amyloid precursor protein (APP)–a protein, which if built up to high levels causes amyloid-β plaques to accumulate in the brain4. At toxic levels, such amyloid accumulation causes characteristics of Alzheimer’s, evidenced by defects in learning and memory.

Many of these animals are useful in that they model pathogenic features of Alzheimer’s, but they do so in young, healthy rodents. And of course we know that Alzheimer’s develops in the elderly brain.

Answering the Call for an Aged Rat
Because the APP transgenic animal is one of the most commonly used AD models, research has focused heavily on the amyloid cascade. However, many clinical trials which have concentrated on amyloid processing have failed. The drugs which were efficacious in animal models simply were not so in human trials.

The fact is: Alzheimer’s is more than the accumulation of plaque. Aging is the single most important contributing factor to the development of disease. For a long time as a result, the scientific community has asked for an aged animal in order to study the effects of the natural aging process on cognition.

The cost to undertake such a program however, is considerable. In addition to many practical barriers, essentially you must start a colony and then wait 20 months before study initiation. Getting a facility with ample capacity and finding the right, experience people who can care for aged rats is not easy.

We came through though and developed a rat model by simply letting Fischer Rats, well, get older. At the age of 20 months (about 60 to 70-years-old in humans), these rats showed cognitive decline and symptoms of Alzheimer’s.

The Morris Water Maze
We can assess learning and memory deficits through a test called the Morris Water Maze. In this test, a rat is placed in a pool of water about two meters in diameter. In the middle of the pool–a few millimeters below the surface–is a hidden platform. Because the rat can’t see it, it can only discover it on accident. When a rat is placed in the pool for the first time, they will swim in random directions, often toward the pool’s perimeter. Over time though, they swim towards the middle and discover the platform. If this test is done repeatedly with the same rat, eventually they will remember the location and find the platform in less time. After enough trials, the rat will swim directly to the platform. With cognitive decline, it takes longer for the aged rats to find the hidden platform. It’s simply harder for them to remember the location.

Efficacy Testing
After rats are subjected to a therapeutic treatment, a variety of efficacy tests can be performed, including testing for biomarkers of inflammation or synaptic function as well as histological evaluations for the accumulation of amyloid plaques. In addition, a metabolic profile of the hippocampus (the structure in the brain largely responsible for memory) can be performed via in vivo 1H-MR spectroscopy. This profile can detect certain metabolites associated with neuronal dysfunction and death, such as glutamate, phosphocreatine, inositol and taurine. Imaging, such as MRI, can be performed as well–to determine the size of the hippocampus and brain volume.

A New Age
An aged rat model for Alzheimer’s provides a natural model of aging and cognitive decline and may be more translatable to humans–compared to other models which focus only on one particular aspect of the disease. However, as discussed, there is no investigational magic bullet and no one model can accommodate the complexity of the human organism or how disease develops within it. Ultimately, the aged rat expands the portfolio of options drug developers have to study Alzheimer’s, getting us one step closer to discovering a cure.

References

  1. 2011 Alzheimer’s Disease Facts and Figures: http://www.alz.org/downloads/Facts_Figures_2011.pdf.
  2. http://www.alzdiscovery.org/index.php/alzheimers-disease.
  3. http://www.ncbi.nlm.nih.gov/pubmed/21943025.
  4. http://www.ncbi.nlm.nih.gov/pubmed/12130773.