Alzheimer’s disease (AD) is the most common neurodegenerative disease. Worldwide, over 55 million people are believed to be living with AD or other dementias. A significant risk factor of AD is sleep disruption in the form of insufficient sleep and sleep fragmentation (SF). We don’t fully understand what mechanisms underlie the relationship between sleep disruption and AD. Some clues that we have, however, are that both sleep loss and early AD show increased amyloid-β (Aβ) deposits and tau phosphorylation in the hippocampus (HC), as well as the loss of locus coeruleus (LC) neurons. There are important differences between human and mouse amyloid-β, such that human Aβ is much more susceptible to the formation of plaques. 

This project aims to characterize the impact of humanized Aβ on tau phosphorylation in the HC in LC projections into forebrain areas. The mice used for this study had undergone 16 weeks of SF, were a year old at the start of SF, and profused at 19 months old. Mice were randomized to be in rested vs. SF conditions, and the sleep fragmentation was set up so that mice were awake for 10 seconds, once per minute, 24 hours a day. The mice were then profused, their brains were cryopreserved and immunohistochemistry was performed. We used AT8 and AT180 antibodies that bind to phosphorylated tau at different sites (serine 202 + threonine 20 and serine 235 + threonine 231, respectively) and are present in AD pathology. Images of the coronal brain sections were taken using the confocal microscope and analyzed using ImageJ software. We observed that chronic sleep disruption results in early phosphorylation of tau in CA1 but does not increase AEP cleaved tau, suggesting that the phosphorylated tau cannot be attributed to CA1 AEP activation. Continuation of this work will help us better understand how significant APP is in the LC relating to sleep loss. Finally, we hope to compare mouse vs. human results in tau as we can expect differences in tau phosphorylation and processing.