. Endogenous beta-amyloid production in presenilin-deficient embryonic mouse fibroblasts. Nat Cell Biol. 2001 Nov;3(11):1030-3. PubMed.

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  1. This is an interesting paper that flies in the face of much research on presenilins. Dr. Checler's group produces data showing that elimination of presenilin 1 and 2 does not inhibit production of Abeta, but does inhibit cleavage of NOTCH to produce the intracellular NOTCH fragment NICD. This paper needs to be evaluated carefully. Many groups, including our own, have observed that eliminating PS1 reduces Abeta production. Several groups have also shown that combined elimination of both PS1 and PS2 virtually eliminates Abeta production. In addition, we know that gamma secretase inhibitors greatly reduce Abeta production. The paper by Armogida and colleagues, suggests the opposite. How to explain this? I am not sure, but it might suggest that regulation of Abeta production is more complicated or has more redundancy than previously assumed. There might be conditions under which production of alternative enzymes capable of cleaving APP to generate Abeta, or alternatively spliced forms of presenilins, are possible. Alternatively, there might be multiple redundant pathways for cleaving APP. Stay tuned!

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