Oregon: New research has identified some of the processes by which molecules
associated with neurological diseases can disrupt the biological clock,
interfere with sleep and activity patterns, and set the stage for a
spiral of health concerns that can include a decreased lifespan and
Alzheimer’s disease.
Previous studies have shown that disruption of the biological clock –
the natural pattern of day-night activity that’s genetically controlled
in many animals – can cause neurodegeneration, loss of motor function
and early death.
The newest results help outline the molecular mechanisms involved,
and show how proteins associated with neurological disease can diminish
the biological clock function and ultimately lead to very serious health
problems, including severe cognitive deterioration. It also confirms
that these risks increase significantly with age.
"The molecular basis underlying biological clock deficits in
Alzheimer's disease has been difficult to tease out," said Matthew
Blake, an OSU faculty research assistant and author of the study. "Only
recently have we been able to utilize our model system to accurately
dissect this mechanism."
This research was done with fruit flies,
which have many genes and biological processes that are similar or
identical to those of humans, retained through millions of years of
evolution. Circadian clocks are so essential to health that they are
found throughout the nervous system and peripheral organs.
Proper function of circadian rhythms has been shown to affect
everything from sleep to stress reaction, feeding patterns, DNA repair,
fertility and even the effectiveness of medications.
“Alzheimer’s disease has always been of interest in this research,
because sleep disruption is one of its earliest symptoms, and almost
everyone with Alzheimer’s has some sleep problems,” said Jadwiga
Giebultowicz, corresponding author of this study, a professor in the
Department of Integrative Biology in the OSU College of Science, and
expert on the biological and genetic underpinnings of the biological
clock.
“This research adds more support to the hypothesis that neurological
damage is a circular process that, in turn, causes more disruption of
the biological clock,” Giebultowicz said. “We’ve identified a new player
in this process, a fragment of the amyloid precursor protein called
AICD, that is able to enter the nucleus of cells and interfere with
central clock function.”
One known cause of Alzheimer’s disease is cleavage of an amyloid
precursor protein, which creates a peptide that’s toxic to neurons. An
enzyme involved is elevated in Alzheimer’s patients. This study took
that process further and showed that increased production of the enzyme,
which in flies is called dBACE, reduced the expression of a core clock
protein.
The results suggest that dBACE acts via dAICD to cause the disruption
of the biological clock and loss of daily sleep and activity cycles.
This disruptive process was much more severe in older flies.
“A general message from this is that normal day-night, sleep and activity cycles are important,” Giebultowicz said.
“There’s evidence that proper sleep allows neuronal repair activity
and the maintenance of neuronal health,” she said. “Since neuronal
damage is a destructive process that can build on itself once it begins,
it’s important that sleep issues should be taken seriously by people
and their doctors, especially as they age.”
Molecular clock oscillations decline with age, Giebultowicz said, and
finding ways to help maintain or restore them might form the basis for a
possible therapy to reduce or prevent the associated health problems.
Collaborators on this research included Eileen Chow in the Department
of Integrative Biology at OSU, and Doris Kretzschmar at the Oregon
Institute of Occupational Health Sciences, an international expert in
the use of fruit flies as a model for neurodegenerative diseases.