Intrathecal amyloid-beta oligomer administration increases tau phosphorylation in the medial temporal lobe in the African green monkey: A nonhuman primate model of Alzheimer's disease.

AIMS: An obstacle to developing new treatment strategies for Alzheimer's disease (AD) has been the inadequate translation of findings in current AD transgenic rodent models to the prediction of clinical outcomes. By contrast, nonhuman primates (NHPs) share a close neurobiology with humans in virtually all aspects relevant to developing a translational AD model. The present investigation used African green monkeys (AGMs) to refine an inducible NHP model of AD based on the administration of amyloid-beta oligomers (AßOs), a key upstream initiator of AD pathology. METHODS: AßOs or vehicle were repeatedly delivered over 4 weeks to age-matched young adult AGMs by intracerebroventricular (ICV) or intrathecal (IT) injections. Induction of AD-like pathology was assessed in subregions of the medial temporal lobe (MTL) by quantitative immunohistochemistry (IHC) using the AT8 antibody to detect hyperphosphorylated tau. Hippocampal volume was measured by magnetic resonance imaging (MRI) scans prior to, and after, intrathecal injections. RESULTS: IT administration of AßOs in young adult AGMs revealed an elevation of tau phosphorylation in the MTL cortical memory circuit compared with controls. The largest increases were detected in the entorhinal cortex that persisted for at least 12 weeks after dosing. MRI scans showed a reduction in hippocampal volume following AßO injections. CONCLUSIONS: Repeated IT delivery of AßOs in young adult AGMs led to an accelerated AD-like neuropathology in MTL, similar to human AD, supporting the value of this translational model to de-risk the clinical trial of diagnostic and therapeutic strategies.

Telemetric uterine contraction model in preterm cynomolgus monkeys.

A telemetric-based model is presented for evaluation of uterine contractions and preterm labor (PTL) in pregnant cynomolgus monkeys. The model allows continuous monitoring of electromyography (EMG) and intrauterine pressure (IUP) as indicators of uterine activity. A pressure sensor was implanted into the amnion of pregnant monkeys on gestational day (GD) 120 +/- 3 and biopotential sensors were attached to the uterus. A telemetry transmitter was placed in a subcuticular pocket located in the flank. Venous catheters were tethered to the next room for dosing and blood sampling without disturbing the conscious animals. EMG and/or IUP were monitored continuously post-operatively. IUP is a reliable parameter for monitoring intrauterine activity, as demonstrated by a close relationship between bursts of activity in the EMG and increases in IUP. Animals close to term showed a basal level of uterine activity during the daytime, with irregular contractions of <10 mmHg. In the night, spontaneous contractions (10-40 mmHg; maximum between 18:00 and 01:00 h) appeared every 3-6 min. Artificial contractions of 15-40 mmHg that mimicked preterm labor were induced at any time of the day by infusion of 5-60 mU oxytocin (OT) per kilogram per hour. These contractions showed a dose-dependent response to OT, and were stable for up to 14 h of constant infusion of OT. Following withdrawal of oxytocin, contractions returned to baseline within 1h. No desensitization of oxytocin-induced contractions was observed when oxytocin was administered daily for up to several weeks. This telemetric model characterizes uterine contractions in non-human primates and provides an excellent method to evaluate pharmacological characteristics of drug candidates intended to treat PTL.