. Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease. J Neurosci. 2006 Jun 7;26(23):6377-85. PubMed.

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  1. To keep apoptosis in check, it may be best to avoid the ups and downs of γ-secretase. Zebrafish lacking the γ-secretase component Pen-2 induce p53-dependent apoptosis throughout the body (Campbell et al., 2006), while mice lacking the Aph-1A component demonstrate increased apoptosis in the neuroepithelium and surrounding mesoderm (Serneels et al., 2005). Now, Alves da Costa et al. have reported that a loss of γ-secretase activity, or its substrates APP and APLP2, reduces the activity of p53. Their report has clearly demonstrated an involvement of γ-secretase in mediating p53-dependent cell death, and the regulation of these pathways is extremely complicated. Previous studies from the same group and others have shown that AD mutant presenilin causes cell death or an increased sensitivity to inducers of apoptosis in cultured cells. The current study has provided further evidence linking mutant presenilin to p53-dependent apoptosis.

    Whether γ-secretase inhibitors could affect p53 function and lead to tumorigenicity is an interesting topic. Alves da Costa et al. have shown that overexpression of the AICD of APP in cultured cells triggers p53-dependent apoptosis, and an earlier report from Jie Shen's group has demonstrated p53-dependent neuronal apoptosis induced by Notch activation (Yang et al., 2004). Since there are more than a dozen γ-secretase substrates that have been identified, apparently AICD and NICD are not the only ICDs derived from γ-secretase cleavage of its substrates. We do not know whether other ICDs could promote/inhibit p53-dependent apoptosis; therefore, some classes of γ-secretase inhibitors may possibly be in a position to prevent tumorigenesis.

    View all comments by Weiming Xia
  2. Didn't you ever think it was odd that there are 155 disease-causing mutations in PS1 but only 10 in PS2? To me, that smacks of a mechanistic difference between the two gene products. And the restriction to 10 PS2 mutations is more consistent with the stringent requirements of a gain-of-function than are the 155 willy-nilly mutations in PS1. So, statistically, it would seem to make sense that PS2 activity has some negative impact on health (e.g., p53 induction) and PS1 a positive one (e.g., p53 suppression).

    View all comments by Steve Barger
  3. It's a very interesting question proposed by Tom Fagan. What is the immediate downstream target of AICD involved in the apoptotic pathway? I have suggested that the AICD target (KAI1) CD82 may be involved at an early stage (see comment [1]). It's of interest that Marreiros et al. report that KAI1 promoter activity is dependent on p53, junB and AP2; however, the Duriez group reports data that KAI1 expression is not significantly modulated by p53. Would the AICD be expected to influence expression of AP2 and junB? If not, might you then expect increased p53?

    See also:

    Comment by Mary Reid on Stellwagen et al., 2006

    View all comments by Mary Reid
  4. I would also like to propose that another p53 target gene which may be involved in AD is brain-specific angiogenesis inhibitor 1(BAI1) and that AICD may be a player in the antiangiogenic pathway. Bescond and Rahmani (1) find that DYRK1A interacts with a brain specific protein, phytanoyl-CoA alpha-hydroxylase-associated protein 1 which is reported to be a binding partner of BAI1.(2) DSCR1 is also overexpressed in AD and the Minani group (3) describes the secondary inhibition of NF-AT signalling as a natural brake in the angiogenic process. Might the beneficial effects of statins be due to the stimulation of angiogenesis?

    View all comments by Mary Reid

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