Jackson Laboratory researchers detect early-stage brain changes in Alzheimer’s disease mouse model

Bar Harbor, Maine—Jackson Laboratory researchers have for the first time used gene profiling to detect early brain changes in the hypothalamus and early changes to insulin signaling in a mouse model of Alzheimer’s disease (AD).

According to Jackson Assistant Professor Gareth Howell, Ph.D., who led the research, "This type of approach will allow us to better understand the earliest stages of Alzheimer's disease, stages that provide the greatest possibility for intervention in human patients."

By the time B-amyloid plaques and Tau tangles are present in human brains, Alzheimer’s disease takes its toll in neurodegeneration and impaired function. To explore the early progression of the disease, the research team used a mouse model for early-onset, familial AD, in which plaques develop in the brain between 4 and 6 months of age.

Working with wild-type (control) mice and the mouse model for AD, the Howell lab measured brain cell gene expression in the mice at 4, 5 and 6 months of age. Using a computational technique known as molecular clustering, they grouped the gene-expression profiles based on degree of similarity.

This is the first study to use molecular clustering, which can yield insights not seen by more traditional analyses, in investigating a mouse model of AD. The researchers noted that the most significant differences in gene expression weren’t seen between AD mutant and wild-type mice at a specific time point, but between samples from mice of different ages. This suggests that aging is a major component of AD progression, even at a relatively young age. The differences between ages were primarily changes in mRNA processing and protein translation and oxidative phosphorylation, both well established age-related processes.

The second most significant differences observed were AD-relevant changes, and interestingly, these changes were hormone-related and implicate early dysfunction in the hypothalamus. "Changes in the hypothalamus appear to be very early in the mouse model of Alzheimer's disease we assessed," lead author Harriet Jackson says. "This is the area of the brain that controls among other things sleep, mood and appetite. Changes in these behaviors are being linked to human Alzheimer's disease, and our study is the first to suggest they may be early diagnostic measures."

The researchers also found that insulin signaling appears to be a critical pathway early in AD. Although this is the first study to suggest it may be critical in early AD, other research has implicated insulin signaling in AD, leading some researchers to categorize AD as "type 3 diabetes." Howell notes, "Insulin signaling can impact multiple aspects of AD symptoms, including tangle formation. Even with the acknowledged limitations of current mouse models, it is exciting to see that our findings relate well with human AD." Howell adds that the approach used in the study "will help us investigate why mouse models don't recapitulate all aspects of human Alzheimer's disease and help us build better mouse models in the future."

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif., and a new genomic medicine institute in Farmington, Conn. It employs more than 1,500 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.

Jackson et al.: "Clustering of transcriptional profiles identifies changes to insulin signaling as an early event in a mouse model of Alzheimer’s disease." BMC Genomics 2013, 14:831.