A hallmark of Alzheimer’s disease (AD) is the accumulation of amyloid beta (Aβ) peptide into plaques in the brain. The role of these plaques in the pathophysiology of disease is unclear, but some treatments that disrupt plaque formation are effective. Secretase inhibitors can disrupt plaque formation but they have toxic side-effects that are ameliorated by intermittent therapy regimens. However, there is concern that Aβ might rapidly accumulate when the inhibitor is withdrawn. Cook et al. determined that the γ-secretase inhibitor (GSI) MK-0752 inhibits Aβ accumulation in rhesus monkeys without an elevation in CNS Aβ accumulation after drug withdrawal. By administering stable isotopes concomitantly with the GSI, they determined that only plasma levels of Aβ rebounded after treatment, whereas CNS levels remained low. During secretase inhibition, an alternate pathway in the CNS metabolized Aβ precursors. This suggests that it may be safe to treat AD transiently with secretase inhibitors.
Cook JJ, Wildsmith KR, Gilberto DB, Holahan MA, Kinney GG, Mathers PD, Michener MS, Price EA, Shearman MS, Simon AJ, et al. (2010). Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound. J Neurosci. 30, 6743– 6750.
