Longitudinal effects on plasma abeta levels of imatinib, a gamma-secretase activating protein inhibitor

Imatinib Mesylate is a competitive tyrosine-kinase inhibitor used in the treatment of multiple types of leukaemia, including Ph+ chronic myelogenous leukaemia (CML). The recent report that Imatinib inhibits gamma-secretase activating protein (gSAP), reducing beta-amyloid- (Abeta) production without affecting Notch-1 cleavage has led to the proposal of a possible application of this drug in AD therapeutics. In fact, one major drawback of Semagacestat, a direct inhibitor of gamma-secretase, was identified in the low Abeta/Notch therapeutic index, with the consequent failure of the phase III trial. Imatinib peripheral administration (20 mg/kg/day) was able to reduce Abeta content in mouse brain. Usually, leukaemia patients receive an average oral dose of 400 mg/day (∼5–6 mg/kg/day). In this longitudinal study we investigated if Imatinib administration in 10 leukemic patients could reduce plasma Abeta1–40 levels. Patients’ blood was sampled prior to treatment (time T0) and after 15, 30, and 60-to-90 days of treatment. Abeta1–40 plasma levels were assessed by ELISA as previously described. No significant reduction in plasma Abeta1–40 was observed at any time point. In fact, ratios to T0 of Abeta1–40 T15-, T30- and T90 were: 1.07 ± 0.39, 1.37 ± 0.59, and 1.48 ± 0.61, respectively, indicating no decrease with Imatinib. While these results are negative at standard dosing of Imatinib for CML, they do not exclude the possibility that Abeta lowering effects might be present at higher doses of this drug or with second generation tyrosine-kinase inhibitors, such as Dasatinib or Nilotinib, which can cross the blood brain barrier more easily. Further exploration of this issue might lead to advances in AD therapeutics