Chronic treatment with anesthetic propofol attenuates β-amyloid protein levels in brain tissues of aged mice

Alzheimer’s disease(AD)is the most common form of dementia.At the present time,however,AD still lacks effective treatments.Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice.Accumulation ofβ-amyloid protein(Aβ)is a major component of the neuropathogenesis of AD dementia and cognitive impairment.We therefore set out to determine the effects of chronic treatment with propofol on Aβlevels in brain tissues of aged mice.Propofol(50 mg/kg)was administrated to aged(18 month-old)wild-type mice once a week for 8 weeks.The brain tissues of mice were harvested one day after the final propofol treatment.The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay(ELISA)and Western blot analysis.Here we report that the propofol treatment reduced Aβ(Aβ40 and Aβ42)levels in the brain tissues of the aged mice.Moreover,the propofol treatment decreased the levels ofβ-site amyloid precursor protein cleaving enzyme(the enzyme for Aβgeneration),and increased the levels of neprilysin(the enzyme for Aβdegradation)in the brain tissues of the aged mice.These results suggested that the chronic treatment with propofol might reduce brain Aβlevels potentially via decreasing brain levels ofβ-site amyloid precursor protein cleaving enzyme,thus decreasing Aβgeneration;and via increasing brain neprilysin levels,thus increasing Aβdegradation.These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research.

RNAi-mediated knock-down of Dab and Numb attenuate Ab levels via g-secretase mediated APP processing

Amyloid-b-protein(Ab),the key component of senile plaques in Alzheimer’s disease(AD)brain,is produced from amyloid precursor protein(APP)by cleavage of b-secretase and then g-secretase.APP adaptor proteins with phosphotyrosine-binding(PTB)domains,including Dab(gene:DAB)and Numb(gene:NUMB),can bind to and interact with the conserved YENPTY-motif in the APP C-terminus.Here we describe,for the first time,the effects of RNAi knock-down of Dab and Numb expression on APP processing and Ab production.RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP(H4-FL-APP cells)or APP-C99(H4-APP-C99 cells)increased levels of APP-C-terminal fragments(APP-CTFs)and lowered Ab levels in both cell lines by inhibiting g-secretase cleavage of APP.Finally,RNAi knock-down of APP also reduced levels of Numb in H4-APP cells.These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD.The notion of attenuating g-secretase cleavage of APP via the APP adaptor proteins,Dab and Numb,is particularly attractive with regard to therapeutic potential,given that side effects of gsecretase inhibition owing to impaired proteolysis of other g-secretase substrates,e.g.Notch,might be avoided.