7-Deoxy-trans-dihydronarciclasine Reduces ß-Amyloid and Ameliorates Memory Impairment in a Transgenic Model of Alzheimer's Disease.

ABSTRACT

The critical pathological feature of Alzheimer's disease (AD) is the accumulation of ß-amyloid (Aß), the main constituent of amyloid plaques. ß-amyloid precursor protein (APP) undergoes amyloidogenic cleavage by ß- and γ-secretase generating Aß at endosomes or non-amyloidogenic processing by α-secretase precluding the production of Aß at the plasma membrane. Recently, several natural products have been widely researched on the prevention of Aß accumulation for AD treatment. We previously reported that Lycoris chejuensis K. Tae et S. Ko (CJ), which originated from Jeju Island in Korea, improved the disrupted memory functions and reduced Aß production in vivo. Here, we further explored the effect of its active component, 7-deoxy-trans-dihydronarciclasine (coded as E144), on Aß generation and the underlying mechanism. Our results showed that E144 reduced the level of APP, especially its mature form, in HeLa cells overexpressing human APP with the Swedish mutation. Concomitantly, E144 decreased the levels of Aß, sAPPß, sAPPα, and C-terminal fragment. In addition, administration of E144 normalized the behavioral deficits in Tg2576 mice, an APP transgenic mouse model of AD. E144 also decreased the Aß and APP levels in the cerebral cortex of Tg2576 mice. Thus, we propose that E144 could be a potential drug candidate for an anti-amyloid disease-modifying AD therapy.