Exercise Improves Brain Tissue Oxygenation in a Mouse Model of Alzheimer’s Disease

Post by Elisa Guma

What's the science?

Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with loss of memory, as well as neuronal cell death due to the aggregation of tangles (formed by misfolded tau protein in neurons), and plaques (formed by a protein amyloid-beta). Further, the vascular system has been shown to be compromised in AD, but it is unclear what role it plays in disease progression and whether it could be a potential treatment target. Voluntary exercise has been identified as an effective means for preserving brain function and preventing cognitive decline in both rodent and human research. However, the oxygenation mechanism through which voluntary exercise affects AD remains unknown. This week in the Neurobiology of Aging, Lu, and colleagues use a novel approach to image brain oxygenation and blood flow in awake mice to investigate whether brain oxygenation is compromised in a mouse model of AD and if voluntary exercise can reverse impairments. 

How did they do it?

The authors used a transgenic AD mouse model, which expresses Amyloid Precursor Protein Presenilin-1 gene mutations that have been identified in humans with AD, and develops cognitive impairments and memory loss at 4.5 months. Tissue oxygenation was measured in AD and wild-type (normal) mice at 3 and 6 months of age, as well as in a group of AD mice who were given a running wheel at 3 months and assessed at 6 months.

The authors used a novel two-photon microscopy system with a phosphorescent lifetime arm, which measures the lifetime of a fluorescent signal as opposed to just identifying its presence, in order to measure tissue oxygenation and cerebral blood flow at a sub-capillary resolution around cortical arterioles, capillaries, and venules in awake mice. Tissue oxygenation was measured using oxygen partial pressure in brain tissue which is affected by variations in blood flow and metabolic demand in different regions. To be able to view the blood vessels in the brain, the authors drilled a hole in the mouse skull (under anesthesia) above the barrel cortex, while keeping the dura mater (a layer of tissue surrounding the brain and spinal cord) intact, and mounted a glass cover over it, keeping a small silicone-covered hole on the side to act as a biocompatible port. 

An oxygen-sensitive dye was injected into the brain tissue via the biocompatible port, and tissue oxygenation was measured using the two-photon phosphorescence lifetime microscopy. This allowed the authors to see how quickly the oxygen-sensitive dye was decaying (an advantage of the phosphorescence lifetime microscopy), to assess how oxygenated the tissue was at a given time. The authors used another kind of imaging technique, Doppler Optical Coherence Tomography, to acquire cerebral blood flow estimates in the blood vessels. During the experiment, the animals could move on a treadmill wheel which allowed free movement of the limbs. Following the awake imaging, the authors collected the brains of their mice and stained them for amyloid plaques, neuronal cell density, and the LRP1 receptor in the cortex, which has been associated with improving amyloid clearance, to determine if exercise was able to reverse AD pathology.

What did they find?

The authors found a decrease in tissue oxygenation over time in the AD mice. Further, there was more heterogeneity of tissue oxygenation indicative of vascular dysfunction both with increased age and due to AD. They also observed more regions of hypoxia or near-hypoxia (low oxygenation) and decreased cerebral blood flow in the AD mice. An increase in amyloid-beta and a decrease in neuronal cell density in the AD mice were also found.

Voluntary exercise for 3 months seemed to reverse all of the observed impairments in vascular function in the AD mice. First, the authors found increased tissue oxygenation and decreased heterogeneity of oxygenation in the AD mice. Exercise also decreased the number of near-hypoxic areas in AD mice and improved cerebral blood flow. At a cellular level, the authors found that exercise decreased the amount of amyloid-beta plaque and reversed the decrease in neuronal cell density. Interestingly, exercise increased the levels of a receptor called LRP1 in the cortex, suggesting that perhaps it may have improved amyloid clearance. Not all mice ran the same amount over the 3 months, so the authors were able to investigate whether the distance ran correlated with the improvement in oxygenation and blood flow; in fact, they found that it correlated with the amount of brain oxygenation and blood flow observed, suggesting that there is a dose-response between the two. 

What's the impact?

This study is the first to measure brain tissue oxygenation and cerebral blood flow in a live awake mouse using a cutting-edge microscopy technique. They show that blood oxygenation and cerebral blood flow are compromised in a mouse model of AD and that voluntary exercise is able to reverse many of these impairments. This suggests that exercise may be an interesting treatment intervention for individuals with dementia. Unfortunately, this work was only performed in male mice; future work should extend this work to female mice as well, as AD is more prevalent in females. 

Xuecogn Lu et al. Voluntary exercise increases brain tissue oxygenation and spatially homogenized oxygen delivery in a mouse model of Alzheimer’s Disease. Neurobiology of Aging (2019). Access the original scientific publication here.