22 January 1998. Researchers trying to study the role of presenilin-1 (PS1) in Alzheimer's pathogenesis have been stymied by the fact that presenilin knockout mice die before birth. Bart De Strooper from the Flemish Institute of Biotechnology in Belgium and colleagues have now succeeded in identifying a normal function of PS1 by studying cultured nerve cells taken from PS1 knockout mice before they die. In the cultured cells, the cleavage of the integral membrane domain of APP by the enzyme γ-secretase was inhibited. This resulted in increased accumulation of carboxyl terminal fragments of APP and a fivefold drop in β amyloid. This is the opposite of the diseased state, so the mutation that leads to disease results in increased PS1 activity. This suggests that inhibiting PS1 might have potential as a treatment for Alzheimer's disease, assuming that it does not also inhibit any vital as yet unknown functions of PS1. The article appears in today's Nature. Stay tuned for an upcoming On-line Journal Club discussion of this paper!-June Kinoshita.

Reference:De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998 Jan 22;391(6665):387-90. Abstract