Gene Expression Profiling in Cells with Enhanced ?-Secretase Activity

Magold, Alexandra I.; Cacquevel, Matthias; Fraering, Patrick C.

The directions in which c-secretase activity can up-and downregulate gene transcription following its cleavage of a variety of substrates is further exemplified by the processing of Amyloid-b (Ab) precursor protein (APP), one of the better-known c-secretase substrates. The successive processing of APP by BACE1 and csecretase indeed leads to the production of Ab peptides (a causative agent in the pathogenesis of Alzheimer's disease (AD)), and APP-intracellular domains (AICDs) which, following associ-ation with the adaptor protein Fe65 and nuclear translocation, are able to suppress the expression of the major Apolipoprotein e (ApoE)/lipoprotein receptor LRP1 by binding directly to its promoter [11] . Thus, APP processing is also involved in the regulation of brain ApoE and cholesterol metabolism through LRP1 [11] . As ApoE4 is the major known genetic risk factor for late onset Alzheimer's disease (LOAD) and since AICD production depends on c-secretase, the latter is implicated in the sporadic form as well. In contrast to LOAD, which correlates directly with age, early onset familial Alzheimer's disease (FAD) is genetic and is mainly caused by mutations in presenilin1 or presenilin2 (PSEN1 or PSEN2), leading to loss of physiological or gain of toxic functions. Murine specific loss of Psen1 in the forebrain has been shown to affect certain aspects of memory [12, 13] . However, it remains difficult to correlate the loss of four murine PSEN alleles with the mild single PSEN allele mutations in FAD [14, 15] . c-Secretase is thus directly or indirectly implicated in the pathogenesis of both FAD and LOAD, making this protease an attractive therapeutic target for the prevention and/or treatment of AD. c-Secretase inhibitors/modulators have indeed reached clinical phase III trials [16] .