Investigation of brain pulsations in Alzheimer’s disease by using a preclinical mouse model

Abstract

Alzheimer’s disease (AD) is a leading form of dementia across the world among elderly. As a fatal neurogenerative disease it causes memory loss, changes in personality and inability to carry out daily tasks. AD is characterized by accumulation of amyloid-β (Aβ) accompanied by hyperphosphorylated tau in the brain, which results in brain deterioration. Difficulty of early detection of AD makes the disease a growing financial burden for healthcare across the world. This creates an urgent need for the discovery of novel biomarkers for early AD.

The accumulation of Aβ in the brain is suggested to result from decline in the brain’s clearance system. Brain clearance preserves cellular homeostasis by draining toxic molecules and metabolites from the brain, and is suggested to be driven by the force of physiological brain pulsations, including cardiovascular, respiratory, and very low frequency (VLF) pulsations.

This Pro Gradu thesis investigates the propagation of different physiological pulsations in AD by using a preclinical mouse model. While all physiological pulsations were found to be strongly expressed in cerebral arteries, they were weakly conducted into the parenchyma. Despite low levels of parenchymal pulsations, pronounced reflection of pulsations were detected in the parenchymal Aβ plaques expressed in AD mouse brains. This indicates that the physical properties of materials are fundamental for the conductivity of physiological brain pulsations, where stiff materials conduct pulse waves relatively better compared to more flexible materials. Arterial VLF pulsations were found to be significantly decreased in AD mice, suggesting arterial smooth muscle cell (SMC) function to play a role in AD pathology.

In conclusion, the results of this study clarify the properties of physiological pulse propagation in AD, giving new insights into the disease pathology and mechanisms behind brain clearance.