Alzheimer's Disease Progression in Amyloid Precursor Protein Mouse Models

That AD is a devastating disorder is indisputable. That little is known about how this disease progresses is fairly clear as well, unfortunately. The problem with AD, as well as with other late-onset neurological disorders, is that researchers cannot readily obtain samples for research until the disease has progressed to a fatal point. Much can be learned from these end-of-life samples, as they show the disease in its most mature state. However, little can be determined from these samples, concerning how AD progresses prior to death. If we are to find a cure for AD, we need to study the pathways that lead to the disease symptoms we wish to avoid.

Since current research strongly indicates that genetic factors are involved in the progression of AD, we want to examine the genes that are active when different symptoms become observable. Unfortunately, investigating the progression of AD requires taking more than a glimpse at the affected tissue; it requires the destruction of significant amounts of affected tissue. This is needed, to extract messenger RNA from the genes, to determine what genes are being expressed in a particular area of the brain. These procedures obviously cannot take place without damaging the patient, and so human subjects are necessarily ruled out for such research purposes.

Our options for research subjects are limited. We can neglect to study genetic behavior in an area of the brain affected by the disease, which would be to neglect to study the development of the disease itself. Another alternative is to use non-human subjects for such investigations, but unfortunately, researchers are not aware of any non-human beings that express AD naturally. Fortunately, however, they have created a model of the human form of AD within mice.

There is much genetic similarity between mice and humans at the DNA level. A vast portion of the genetic structure is the same between the two species, and an even higher correlation exists between the proteins found in the two. In addition, mice are easy care for, allowing researchers to readily maintain them. Mice have a naturally short life span, which provides for a faster progression of the disease, allowing for more and faster studies. Perhaps most importantly, researchers can ethically sacrifice mice in a way that could not be done with humans. The end result is that with a mouse model of AD, researchers can, glimpse into the genetic expression of affected brain cells throughout the progression of the disease.

To understand the progression of AD, researchers in the Reddy laboratory are studying transgenic mouse models as a source for research subjects. In this model, a human AD gene (amyloid precursor protein) was introduced into mice. These "transgenic" mice mimic faithfully the human pathological features that characterize human AD, such as senile plaques and learning and memory deficits.

There have been several transgenic mouse models created to study the progression of AD. The Reddy laboratory is currently using a transgenic mouse model, with a focus on the amyloid precursor protein, to study how gene expressions in the brain change during the progression of the disease and how these changes relate to learning and memory deficits. This study involves determining gene expressions in the brain, in other words, determining how genes in the brain reveal their mutations during the progression of AD.

To measure gene expression levels in AD mouse models, the Reddy laboratory uses gene chip technology (also called DNA chip, and cDNA microarray techniques). Gene chip technology is a research method that measures messenger RNA expression for thousands of genes in a single experiment. With gene chip techniques, it is possible to measure messenger RNA for thousands of genes in a single experiment. OHSU has two gene chip facilities, and the Reddy laboratory uses one of the facilities.

Gene chip technology can help us to understand the genes responsible for early cellular changes involved in AD, by studying brain before the mice develop pathological changes, such as plaques, and studying brain after these these changes occur. This technology can also help us to understand how gene expressions change during the progression of AD in mice. This understanding of the progression of AD may help us to develop therapeutic interventions that will delay or even prevent AD.

This document was created for the neurogenetics laboratory run by P. H. Reddy, Ph.D. in the NSI of OHSU. Page last updated: 25 Sept 2001.