Hussein N. Yassine, United States of America
University Southern California Keck School of MedicineAuthor Of 1 Presentation
CS6253 ABCA1 AGONIST TREATMENT IN JUVENILE CYNOMOLGUS MONKEYS REDUCES CSF AΒ42 AND INCREASES PLASMA AΒ42 IN DOSE-RESPONSE MANNER
Abstract
Aims
The apolipoprotein E (APOE) ε4 is associated with increased AD risk and no effective treatment exists. The apoE4 protein has impaired interaction with astrocyte’s ATP-binding cassette transporter A1 (ABCA1) resulting in: a) poor cholesterol efflux, and b) build-up of residual cholesterol in lipid rafts, impeding astrocyte function (Rawat 2019) and increasing neuron cell death (Voskuhl 2018). Cynomolgus monkeys (cynos) have arginine in the critical 112 and 158 positions (like hu apoE4) but not in the 61 position, a 93% homology with human apoE, as well as lipid and amyloid metabolism similar to humans, making cynos a representative model for humans. In a dose-range finding toxicology study in 2-year old cynos, we explored effects of CS6253 ABCA1 agonist treatment on CSF and blood amyloid markers.
Methods
CS6253 was administered iv at 0 (control), 75, 150 and 225 mg/kg (n=2/sex/group) 5 times over 10 days. CSF was collected before treatment and 6 hours after the 5th/last dosing. CSF and plasma Aβ42 and Aβ40 were analyzed by SIMOA, CSF APP and amyloid protein complex2B1 (AP2B1) by mass spectrometry.
Results
CS6253 treatment decreased CSF levels of Aβ42, Aβ40, APP and AP2B1 and increased plasma Aβ42, Aβ40, both following dose-response pattern, see Figures.
Conclusions
The CS6253 ABCA1 agonist reductions of Aβ42, Aβ40, APP and AP2B1 in CSF of juvenile cynos are consistent with previous finding in apoE4 mice models where brain Aβ42 (and P-tau) was reduced, AD pathology was prevented, and cognition improved. Studies in human APOE ε4 carriers are needed to corroborate these findings.