P1–101: Ablation of striatal dopamine exacerbates cognitive impairment in a mouse model of Alzheimer's disease

Background: Recently, there has been increased recognition that Parkinson’s disease (PD) and Alzheimer’s disease (AD), once thought to be wholly independent syndromes, have common pathogenic mechanisms and often coexist on a spectrum of neurodegenerative diseases. Patients diagnosed with PD have been found to have 5-8 fold increased risk for developing Alzheimer’s-like pathology as compared with healthy adults, and dopaminergic agonists have been found to be protective against amyloid toxicity in certain cell culture systems. Additionally, recent studies have suggested that the dopamine system may play a role in regulating amyloid metabolism itself. We hypothesized that impairment of the dopamine system would exacerbate AD-like behavior and pathology in mice. Methods:Methods: To determine the effect of dopamine ablation on the cognitive and pathological effects of AD, APPSWE/PS1D9 mice received bilateral injections of the dopaminergic neurotoxin 6-hydroxydopamine. Animals were tested in a modified Barnes maze protocol and a water t-maze protocol at different ages to determine the onset and extent of cognitive impairment. Amyloid b will be measured in the cerebral cortex, hippocampus, and striatum of 12-month-old mice after behavioral testing is completed. Additionally, to determine whether dopaminergic stimulation is protective against Ab 42 toxicity, medium spiny neuron cultures were pretreated with increasing doses of the D1 receptor agonist SKF81927 and the D2 receptor agonist quinpirole before being treated with oligomerized Ab 42. Neuronal health was determined by branch order and dendrite length. Results: AD mice that received 6OHDA injections showed significant impairment in Barnes maze performance at an earlier age than WT or vehicle controls. Additionally, at 12 months of age AD-6OHDA mice demonstrated worse behavioral flexibility in a task-switch phase of the water t-maze than other groups, despite no impairment in learning the original paradigm. Murine medium spiny neurons demonstrated concentration-dependent toxic response to Ab 42, an effect that was partially reversed by dopaminergic agonists. Conclusions: Conclusions: Depletion of dopamine in the striatum exacerbated the cognitive impairment seen in a mouse model of Alzheimer’s disease. This behavioral phenomenon may be due to a protective effect of dopaminergic innervation against the toxic effects of amyloid b on striatal neurons.