Treatment of mice with tyrosine kinase inhibitors (TKI) such as Gleevec lowers plasma levels of amyloid beta peptides (Abeta) in mice

Considerable evidence exists that increased levels of Abeta peptides (Abeta) augment the risk of Alzheimer's disease (AD). Imatinib, a tyrosine inhibitor (TKI), has been shown in mice to decrease synthesis of Abeta in vitro and in vivo although it poorly crosses the blood-brain barrier. Recently, JG Sutcliffe suggested that cerebral levels of Abeta are regulated in peripheral tissues. If TKI decreased Abeta production in humans and lowered its plasma levels it might complement the therapeutic efficacy of intravenous immunoglobulin (IVIg) now being studied in AD. Levels of Abeta40 and Abeta42 were measured in coded plasma samples from patients with chronic myeloid leukemia (CML) treated with or without TKI and from healthy age-matched individuals not receiving TKI. Plasma was frozen at -80C until assayed using a sensitive ELISA with high avidity rabbit monoclonal antibodies specific for Abeta40 or Abeta42. Plasma Abeta peptide levels were measured in 10 bcr-abl+ CML patients in cytogenetic remission and 1 bcr-abl+ ALL patient in remission treated with TKIs for one to 9 years. Mean plasma Abeta40 in this group was 176 +/- 50 pg/ml and mean Abeta42 74 +/- 41 pg/ml. These values were significantly lower (p < 0.011, two-tailed rank-sum test) than in 3 plasmas CML patients not treated with TKI (mean Abeta40 344 +/- 32; mean Abeta42, 204 +/- 40 pg/ml). Plasma Abeta peptides in the 11 TKI-treated patients were also significantly lower (p < 0.048) than in 6 healthy individuals not receiving TKIs (mean Abeta40, 258 +/- 45 and mean Abeta42, 125 +/- 47 pg/ml). Patients with bcr-abl+ disease treated with TKIs for as long as 9 years had significantly lower plasma levels of Abeta40 and Abeta42 than CML patients not receiving TKI or normal individuals. This is the first report that TKI therapy in humans is associated with a reduction in plasma levels in Abeta 40 and Abeta 42. Our data imply that adding TKIs to other therapies for AD such as IVIg might offer a uniquely effective pairing of drugs, one clearing Abeta from the brain and another inhibiting Abeta synthesis in AD patients.