Basic NeuroscienceCisterna magna cannulated repeated CSF sampling rat model - effects of a gamma-secretase inhibitor on Aβ levels

Cerebrospinal fluid (CSF) provides a window into central nervous system (CNS) physiology and pathophysiology in human neurodegenerative conditions such as Alzheimer's disease. Changes in CSF bioanalytes also provide a direct readout of target engagement in the CNS following pharmacological interventions in clinical trials. Given the importance of tracking CNS bioanalytes in drug discovery, we have developed a novel cisterna magna cannulated rat model for repeated CSF sampling and used it to assess an amyloid beta (Aβ) lowering agent. The surgically implanted cisterna magna cannula was patent over a period of 1-2 weeks and enabled repeated sampling of CSF (volume of ∼30-50 μL/sample) from each rat. CSF Aβ40 levels showed good intra-animal variability across time points and inter-animal variability within a time point. Peripheral treatment with a gamma-secretase inhibitor (GSI) led to a rapid and robust decline in CSF Aβ40 levels that returned to baseline over 24-96 h after dosing. Terminal brain, CSF and plasma Aβ levels measured at 24 h after dosing demonstrated robust Aβ lowering and showed excellent correlation across these compartments. These results are the first pharmacological validation of the repeated CSF sampling rat model for Aβ lowering agents. This model can have broad applicability in pharmacological evaluation for diverse CNS targets.

► Developed a cisterna magna cannulated rat model for repeated CSF sampling. ► Robust intra-animal and inter-animal consistency in CSF Aβ levels over time. ► Robust CSF Aβ lowering with gamma-secretase inhibitor treatment over time. ► Excellent correlation of terminal Aβ levels between CSF, brain, and plasma. ► Broad applicability in CSF PK-PD and biomarker studies for novel CNS targets.