A-Secretase shift

Nevertheless, collateral functions for nicotine have been found to (1) promote an a-secretase shift, leading to release of neurotropic and neuroprotective sAPPa, and (2) prevent Aj3 and CTFj3 neurotoxicity (234,... 

Epidemiological observations are beginning to be confirmed in vitro. For example, in APP751-transfected HEK 293 cells the elevated, by various means, level of cholesterol caused a dramatic reduction in secretion of the soluble APP fragment sAPPa (84). At the cellular level it is by now proved that cholesterol depletion (by 70%) in cultured neurons by combination of lovastatin treatment and methyl-jS-cyclodextrin extraction reduces production of Aj8 below detectable levels (85) by shifting the APP processing to a-secretase (86). 

Pitsi and Octave (196) demonstrated that the expression of PSl, which binds C99, not only increases the production of ABP but also increases the intracellular levels of C99 to the same extent. A functional inhibitor of y-secretase does not alter the ability of PSl to increase the intracellular levels of C99, suggesting that the binding of PSl to C99 does not necessarily lead to its immediate cleavage by y-secretase, which could be a spatiotemporally regulated or an induced event (196). Missense mutations in PSl and PS2 shift the ratio of ABPl-40/ABPl-42 to favor ABPl-42. A possible explanation of this outcome is that mutant PS alters the specificity of y-secretase to favor production of ABPl-42 at the expense of ABPl-40. 

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