| abstract | Alzheimer's disease (AD) is a neurodegenerative disorder characterized primarily by progressive memory loss. It is estimated
to afflict nearly 47 million people worldwide, and its prevalence is expected to triple within 35 years. Within the last decade, 99.6% of drugs targeting this
disease have failed in clinical trials, and those few that have succeeded have mild effects, at best. Recently, the serine/threonine kinase PKC-ε has become
a target for drug development in AD. The kinase has been shown to play a role in critical processes related to AD pathology, including neurite outgrowth,
synaptogenesis, and long-term potentiation. The linoleic acid derivative 8-[2-(2-pentylcyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) specifically
activates PKC-ε and has been shown to be beneficial for cognitive and molecular pathology in transgenic models of AD. However, transgenic models have
many issues when it comes to the drug development process. As such, we have tested the therapeutic potential of DCP-LA in the FAB rat model, which is a
pharmacological AD model that focuses on the role of oxidative stress in the molecular pathology of the disease. The goals of this experiment were to
specifically assess the effects of DCP-LA on learning, memory, neuronal health, and synaptic density. To measure learning and memory, rats were trained
to complete the Morris water maze. To measure neuronal health in the hippocampus, immunostaining was performed against the neuronal marker NeuN. To measure
synaptic density in the hippocampus, immunostaining was performed against the synaptic marker synaptophysin. We report a decrease in performance for FAB
rats in both the learning and memory tasks in the Morris water maze. Treatment with DCP-LA (3mg/kg) restored performance on both tasks to the level of control
animals. There was significant neurodegeneration observed in the CA1, CA3, and dentate gyrus regions of FAB rats compared to all other groups. DCP-LA treatment
partially restored the density of healthy neurons, but not to back control levels in the CA1 and CA3. FAB rats also exhibited significant loss of synaptic
density in all three hippocampal region tested, which was recovered to control levels by DCP-LA treatment. Together, these data suggest that DCP-LA treatment
is able to reverse learning and memory deficits and improve neuronal and synaptic health in FAB rats. While this certainly suggests that DCP-LA has potential
to be used in the human disease, more research is required to determine key safety data, such as systemic toxicity, optimal dosages, and treatment windows. |
