An Alternative Secretase Cleavage Produces Soluble Alzheimer Amyloid Precursor Protein Containing a Potentially Amyloidogenic Sequence

Abstract

Cell culture studies have shown that the Alzheimer amyloid precursor protein (APP) is secreted after full‐length APP is cleaved by a putative secretase at the Lys16‐Leu17 bond (secretase cleavage I) of the amyloid peptide sequence. Because this cleavage event is incompatible with amyloid production, it has been assumed that secreted APP cannot serve as a precursor of the amyloid depositions observed in Alzheimer's disease. Here we show that in neuronally differentiated PC12 cells and human kidney 293 cell cultures a portion of the secreted extracytoplasmic APP reacted specifically with both a monoclonal antibody recognizing amyloid protein residues Leu17‐Val24 and a polyclonal antiserum directed against amyloid protein residues Ala21‐Lys28. Furthermore, this APP failed to react with antisera recognizing the cytoplasmic domain of the full‐length protein. These data indicate the presence of an alternative APP secretase cleavage site (secretase cleavage II), C‐terminal to the predominant secretase cleavage I. Depending on the exact location of cleavage site II, potentially amyloidogenic secreted APP species may be produced.

Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

“…p75 NTR as a substrate for γ-secretase [26,33,39] adds to a growing list of proteins shown to be substrates for γ-secretase cleavage, including APP [52–54], Notch [55,56], and Notch ligands Delta1 and Jagged2 [57], ErbB4 [58], CD44 [59,60], and E-cadherin [61,62]. Our in vitro data and the recent application of γ-secretase inhibitors (egs.LY-450139 and LY-411575) in advanced clinical trials for Alzheimer disease [63–65] prompted us to investigate the use of γ-secretase inhibitors to treat highly invasive gliomas.…”

ADAM-17: the enzyme that does it all

“…The intracellular fragment induces intracellular Ca 2+ signaling (Leissring et al, 2002). This process results in a soluble extracellular fragment that does not contribute to amyloid plaque formation (Anderson et al, 1992, Kojro and Fahrenholz, 2005). In contrast, decreased activity or lack of α-secretases allows β-secretase to cleave the extracellular module of APP at a more distal region which will result in formation of the amyloidogenic β peptide (Yan et al, 1999).…”

Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

“…This idea was reinforced by the mapping of the β-amyloid cleavage enzyme 2 (BACE2) to the DS critical region of chromosome 21 [72], which in concert with the γ-secretase complex is essential for cleavage of Aβ 40 and 42 from APP [73,74]. On the other hand, α-secretase, which is not encoded on chromosome 21, plays an important function as it cleaves extracellular APP in the middle of the Aβ portion, preventing release of Aβ [75-77], acting as a neuroprotectant [78], and promoting activation of microglia and induction of synthesis and release of the proinflammatory cytokine IL-1β [20]. If BACE2 induced shedding of IL-1 receptor2 (IL-1R2) [79] acts to avail the brain of decoy receptors for IL-1, the levels of IL-1 may be reduced and therefore neuroinflammation responses in DS and AD dampened.…”