Elsevier

Neuroscience

Volume 57, Issue 4, December 1993, Pages 873-877
Neuroscience

Regulated cleavage of alzheimer β-amyloid precursor protein in the absence of the cytoplasmic tail

https://doi.org/10.1016/0306-4522(93)90031-AGet rights and content

Abstract

Alzheimer β-amyloid precursor protein can be phosphorylated on residues Thr654, Ser655 and Thr668 on its cytoplasmic domain. Proteolytic cleavage of the amyloid precursor protein and release of the amyloid precursor protein ectodomain into the medium of cultured cells can be activated by phorbol esters which stimulate protein kinase C. In the present study, using mutated amyloid precursor protein, we show that phosphorylation of cytoplasmic residues is not required for the phorbol ester-activated cleavage and release of the amyloid precursor protein ectodomain. Remarkably, deletion of the entire amyloid precursor protein cytoplasmic tail had no effect on the phorbol ester-activated cleavage/release. The results indicate that activation of amyloid precursor protein cleavage/release by protein kinase C involves phosphorylation of some component of the processing pathway, instead of or in addition to the cytoplasmic tail of the amyloid precursor protein.

References (17)

There are more references available in the full text version of this article.

Cited by (67)

  • Role of tyrosine phosphorylation in the regulation of cleavage secretion of angiotensin-converting enzyme

    2004, Journal of Biological Chemistry
    Citation Excerpt :

    The 8-kDa C-tail fragment that was left in the cell after the ectodomain of ACE was cleaved off was not tyrosine-phosphorylated, and the cleavage secretion of a cytoplasmic tail-deleted mutant ACE was also enhanced by pervanadate, indicating that the presence of the cytoplasmic tail is not essential for this response (Fig. 5). Similar to ACE shedding, transforming growth factor α, β-amyloid precursor protein, syndecan (37, 38), or L1 adhesion molecule shedding does not appear to depend on the cytoplasmic tail sequences (39). The cytoplasmic domain of l-selectin, on the contrary, seems to play a role in regulating its susceptibility to ectodomain shedding (40).

  • Stimulation of β-amyloid precursor protein α-processing by phorbol ester involves calcium and calpain activation

    2004, Biochemical and Biophysical Research Communications
    Citation Excerpt :

    Perhaps because phorbol esters are best known for PKC activation, many studies have focused on PKC as a key mediator. But earlier studies have found that although phorbol esters phosphorylate the intracellular domain of APP [39], deletion of this domain does not abolish the stimulated APP secretion [5,17]. In turn, more recent studies have looked beyond and suggested several new mechanisms.

  • Platelet-derived growth factor induces the β-γ-secretase-mediated cleavage of Alzheimer's amyloid precursor protein through a Src-Rac-dependent pathway

    2003, Journal of Biological Chemistry
    Citation Excerpt :

    On the other hand, there are experimental results suggesting that phosphorylation of APP does not affect its processing. In fact, it was well documented that APP is phosphorylated on Ser and Thr in vitro and in vivo (59), but these post-translational modifications are not involved in the regulation of APP cleavage (60). APP is also phosphorylated at the level of Tyr-682 (APP695isoform numbering) of its intracellular domain (8).

  • Molecular basis for anti-amyloid therapy in the prevention and treatment of Alzheimer's disease

    2002, Neurobiology of Aging
    Citation Excerpt :

    Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, also increases APP proteolysis and release via the alpha-secretase pathway (Fig. 3; [9]), and it has recently been shown in primary neuronal cultures that protein phosphatase inhibition by okadaic acid is much more effective in lowering A-beta production than is PKC activation [27]. Thus, either stimulation of PKC or inhibition of protein phosphatases 1 and 2A is sufficient to produce a dramatic acceleration of nonamyloidogenic APP degradation and diminished generation of A-beta in virtually every situation tested to date, including primary neuronal cultures and rodent brain in vivo (Figs. 1–3; [10–31,56]). This phenomenon is sometimes referred to as “regulated cleavage of APP” or “reciprocal regulation of APP metabolism”; i.e. when certain signals are activated, alpha-secretase cleavage increases and (Asp1- and Glu11-beta-secretase cleavages decrease (Figs. 1–3).

View all citing articles on Scopus
View full text