Abstract
Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity), we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila. Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs), Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging.
Highlights
Neuronal dysfunction and cell death are hallmarks of agerelated neurodegenerative disorders, such as Alzheimer’s disease
In order to understand the molecular mechanisms underlying age-related alterations of neural circuitry, we focused on caspase-3, a cysteine protease that induces apoptotic cell death, using the fruit fly Drosophila melanogaster, a model often used to study aging due to a short lifespan of approximately 30–60 days
These findings suggest that caspase-3 plays an active role in producing age-related alterations to neuronal physiology and circuit function associated with animal behavior
Summary
Neuronal dysfunction and cell death are hallmarks of agerelated neurodegenerative disorders, such as Alzheimer’s disease. Knockout mice lacking caspase-3, caspase-9, or the caspase activator, apaf-1, all exhibit reduced neuronal apoptosis and brain malformation [6,7,8,9,10,11], indicating that caspases are essential for normal brain development. In addition to their role in apoptosis, non-apoptotic roles for caspases, in the nervous system, are being reported in vivo [12]. The essential role of caspases in developing and adult brains has been documented, the in vivo activation pattern of caspases has not yet been systematically investigated
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