Samuel Barlow and Dr. Jonathan Wisco, Physiology and Developmental Biology

Introduction

Alzheimer’s Disease (AD) is one of the highest causes of death in the United States. After the age of 65, the chance of getting Alzheimer’s doubles every five years. As the average lifespan of Americans increases, the importance of understanding AD and finding more efficient ways to treat it increases as well. The earlier AD is treated, the more effectively we are able to treat it. Non-heme iron (Fe) has been shown to spatially correlate with Abeta. Since Fe causes a signal dropout in susceptibility-weighted Magnetic Resonance Imaging (MRI), this imaging modality could possibly be used as a way to detect Abeta in the brain. The purpose of our research was to confirm that iron correlated spatially to Abeta in the entorhinal cortex. Also, we wanted to see if HP-tau also correlated to iron in the entorhinal cortex. If tau is shown to co-localize to iron, this may be a potential way to detect AD in its earliest stages. Also, we needed more data and images to further Dr. Wisco’s previous research.

Methodology

We stained entorhinal cortex regions that were sectioned 6 microns thick for Abeta, HP-tau, and Fe. Each section was scanned and viewed with Leica Digital Image Hub. We then exported images of the entorhinal cortex from different sections to Adobe Photoshop CS6, pseudo-colored images of the different stains, and aligned the images of the different stains on top of each other with a manual affine registration and elastic warp. We then qualitatively analyzed the spatial overlap of the three stains. We obtained our data from entorhinal cortex regions of five deceased subjects: a 76-year-old (yo) F with cerebrovascular disease (CVD), AD Braak Stage VI and diffuse Lewy Body Disease; a 96 yo F with CVD and Braak VI; one 70 yo M with Braak VI only; a 86 yo M with Braak IV-V; and our control, an 81 yo F who had scleroderma and pulmonary hypertension.

Results

We confirmed that Fe spatially correlates with Abeta, but much less so with HP-tau in the entorhinal cortex in the Braak IV-V subject. The 81 yo F control did not show spatial correlation between Fe, Abeta, or HP-tau as expected. However, in the Braak VI subject, this trend was reversed: we saw more correlation between Fe and HP-tau than between Fe and Abeta.

Discussion

There are still very few effective treatments for AD and many of these treatments focus on slowing down the effects of the disease, not curing it. The effects of AD are usually not seen until AD has progressed for a long time. Finding a way to diagnose AD early is an important step in curing the disease. The entorhinal cortex is one of the first regions of the brain to exhibit AD pathology – the buildup of Amyloid-beta plaques (Abeta) and hyper-phosphorylated Tau protein tangles (HP-tau).

Conclusion

A signal dropout in the entorhinal cortex due to Abeta using MRI may be a method to diagnose AD in its earlier stages. A signal dropout in the entorhinal cortex due to HP-tau could be a potential diagnosis for AD in its later stages. In the future, we want to look at the correlation of iron to Abeta and HP-tau in earlier stages of AD.