Novel mechanism behind Alzheimer’s-related circadian rhythm disruptions

Alzheimer’s disease (AD), a progressive and highly disruptive neurodegenerative condition, leads to a severe decrease in cognitive capabilities. Though the root cause of AD is unclear, it is known that increased levels of amyloid-β—a cleavage product of the amyloid precursor protein (APP)—are associated with development of the disease. Additionally, disruptions of sleep cycles are known to occur in AD patients, with increased sleep activity during daytime and increased wakefulness at night. These sleep disruptions suggest a link between the circadian clock and AD pathogenesis.

In a recent publication in the journal Neurobiology of Disease, Blake et al. manipulated APP-like (APPL) protein (an ortholog of human APP) cleavage in Drosophila melanogaster to study potential impacts on circadian clock function. The investigators used Drosophila due to the highly conserved nature of the protein/enzyme complexes between fruit flies, rodents, and humans—notably a group of α and ϒ-secretase complexes, dBACE, Kuzibanian (Kuz), and Presenilin.

In the work, the researchers used longevity, a climbing assay, locomotor activity and rhythmicity of locomotor activity to assess behavioral impacts of their manipulations. Immunohistochemistry was used to assess the level of PERIOD (PER), a marker of molecular oscillations in central pacemaker neurons which underlie behavioral circadian rhythms. First, dBACE levels were increased by over-expressing α-secretase. This led to age-related disruptions in rest-activity rhythms in the flies, shortened longevity, and decreased power of their rhythmic movements. Additionally, dBACE over-expression led to lowered expression of PER, suggesting that increased levels of dBACE disrupt both the molecular circadian clock and the behavioral activity-rest cycle.

Interestingly, when the authors over-expressed KUZ, they also found that rest-activity rhythms were disrupted, with Drosophila showing decreased rhythmic power. Taken together, these two separate experiments suggested a common product originating from cleavage of APPL in both α and β pathways. To test this, researchers over-expressed the intracellular domain of APPL. This severely disrupted rest-activity rhythms when expressed in central pacemaker neurons, and showed age-dependent disruption of activity when expressed pan-neuronally. However, full-length APPL expression was protective against these deficits.

These results strongly implicate the APPL Drosophila amyloid intracellular domain in moderating both molecular circadian clock and the behavioral manifestation of them, in terms of rest-activity rhythms. Interestingly, the over-expression of full length APPL was protective against age-related circadian disruptions. Taken together, these data suggest a novel mechanism for understanding circadian disruptions experienced by AD patients, and potentially, a novel pathway on which to focus attention of therapeutic research.

Publication

1. Blake MR, Holbrook SD, Kotwica-Rolinska J, Chow ES, Kretzschmar D, Giebultowicz JM (2015) Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila. Neurobiology of Disease 85(4):1-14. doi: 10.1016/j.nbd.2015.02.012