Boost Memory in Alzheimer's Patients with Exercise

Alzheimer's disease (AD) is a neurodegenerative condition that typically affects older people and is the leading cause of dementia worldwide. AD is characterized by progressive cognitive impairment caused by a decades-long process that leads to neuronal dysfunction. The global prevalence of AD is projected to triple by 2050 and currently there are limited strategies to prevent or slow down the progression of this devastating condition.

Dr. Zheng Sun, associate professor of medicine, endocrinology; Dr. Hu Chen, assistant professor of pediatrics, and their colleagues at Baylor College of Medicine have been studying the effects of exercise in an Alzheimer's disease mouse model. In this interview, Sun talks about his work, which is published in Alzheimer's & Dementia, the flagship journal of the Alzheimer's Association, and offers insights into potential new ways to prevent or treat this condition.

Why did you decide to study this topic?

Physical exercise is known to reduce the risk or slow the progression of Alzheimer's disease. We wanted to understand the underlying mechanism, which might provide new ways to treat the condition.

How did you approach this study?

We investigated how regular wheel-running exercise changes gene expression and chromatin accessibility—the latter refers to the physical accessibility of genetic information encoded in the cell's DNA. We studied this in different cell types of the mouse hippocampus, a brain region important for learning and new memory formation.

How did you conduct the study?

We used single-nucleus RNA-seq to determine which genes were expressed differently in the hippocampus after exercise and assessed chromatin accessibility with single-nucleus Assay for Transposase-Accessible Chromatin. We studied both factors in normal healthy mice and in an AD mouse model carrying amyloid precursor protein (APP) mutations (APP mice). The AD mouse model mimics characteristics of human familial Alzheimer's disease, including amyloid deposition in the brain and memory problems.

We compared normal and APP mice that had been wheel-running regularly for months with those that did not exercise. We also compared the animals' behavior in memory tests.

We found that exercise improves learning and memory and induces changes in gene expression in the hippocampus. Compared to normal mice, APP mice had less active cellular pathways in the hippocampus, particularly those involving epidermal growth factor receptor (EGFR) and insulin. Importantly, wheel-running exercise counteracted these changes by enhancing EGFR and insulin signaling in the APP mouse. Blocking the EGFR and insulin signaling with drugs blocked the beneficial effects of exercise on memory tests.

We also found that exercise leads to elevated blood levels of heparin-binding EGF (HB-EGF) and tested whether this growth factor was involved in the beneficial effects of exercise on memory. After months of intranasal administration of HB-EGF, the sedentary APP mice improved memory and reduced amyloid deposition in the brain. These findings support the fact that HB-EGF contributes to the memory-enhancing effects of exercise.

These findings are very exciting. What are the implications?

Our study suggests that the EGFR/insulin-related pathway is involved in the benefits physical exercise has on cognitive processes in the context of Alzheimer's disease, opening new possibilities for future treatments to prevent or treat the condition. The results also provide insight into the inverse relationship between cancer and Alzheimer's disease, as EGFR signaling is associated with pro-proliferative and cancer-causing effects, whereas Alzheimer's disease is more closely linked to cellular senescence.

Where does your research go from here?

On the basic science side, an important next step is identifying other players that drive exercise-induced responses and determining how these factors are regulated during the process. A potential long-term clinical direction is to explore whether intranasal administration of HB-EGF could provide preventive or therapeutic benefits for individuals at high risk of Alzheimer's disease. Of course, more laboratory and pre-clinical studies in animal models are needed before testing this possibility.