Abstract
The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)—induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.
Highlights
Alzheimer’s disease (AD), the most common form of dementia, is a neurodegenerative disorder clinically characterized by progressive deterioration of cognitive and behavioral function
While the exact etiology of AD is not yet determined, a cascade of pathophysiological events takes place causing neuronal loss, synaptic dysfunction and neurotransmitter deficiency as the disease progresses. This on-going event impairs crucial memory-related structures, including hippocampus and entorhinal cortex, association cortices and the cerebral default network, causing regional and diffuse neuronal loss and atrophy [4,5]. This pathological event causes the functional deterioration of neurotransmitter system, leading to a decreased amount of acetylcholine, and activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in almost the entire neocortex [6]
In a previous study in adult mouse lemurs, we effectively demonstrated the disruptive effects of the SD on spatial memory retrieval, a cognitive function that is affected in AD patients as the disease progresses [41]
Summary
Alzheimer’s disease (AD), the most common form of dementia, is a neurodegenerative disorder clinically characterized by progressive deterioration of cognitive and behavioral function. While the exact etiology of AD is not yet determined, a cascade of pathophysiological events takes place causing neuronal loss, synaptic dysfunction and neurotransmitter deficiency as the disease progresses This on-going event impairs crucial memory-related structures, including hippocampus and entorhinal cortex, association cortices and the cerebral default network, causing regional and diffuse neuronal loss and atrophy [4,5]. This pathological event causes the functional deterioration of neurotransmitter system, leading to a decreased amount of acetylcholine, and activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in almost the entire neocortex [6]. Impairments in the glutamate neurotransmission system, on the other hand, mediate oxidative stress and excitotoxicity [7,8], resulting in cellular injury and apoptotic cell death
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