. In vivo olfactory model of APP-induced neurodegeneration reveals a reversible cell-autonomous function. J Neurosci. 2011 Sep 28;31(39):13699-704. PubMed.

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  1. In my view, the importance of this study lies in the finding that APP-induced neurodegeneration is cell autonomous. This study makes clever use of cell-specific promoters to show that only the APP-overexpressing cells undergo apoptosis while the neighboring, non-expressing cells remain unharmed. The authors do not speculate on the mechanism of APP-induced neurodegeneration, but the most conservative interpretation of their data would suggest that the intracellular domain of APP is required for the observed lethal effect.

    Indeed, overexpression of APP intracellular domain (AICD) in vivo results in hippocampal neurodegeneration (1) and reduced neurogenesis (2) in transgenic mice. Also, overexpression of AICD has been shown to induce apoptosis in vitro in neuronal cells (3). Germane to the present observations, multiple lines of investigation (4-6) show that AICD is predominantly generated by β-secretase processing of APP.

    Since the transgenic mice used in the study by Cheng et al. expressed Swedish mutant APP (which preferentially undergoes β-processing), it is likely that the APP-overexpressing cells that underwent apoptosis/neurodegeneration had higher levels of AICD. Thus, there is no need to invoke a soluble factor, Aβ or otherwise (7), in the cell-autologous mechanism of APP-induced neurodegeneration reported here.

    References:

    . Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18367-72. PubMed.

    . APP intracellular domain impairs adult neurogenesis in transgenic mice by inducing neuroinflammation. PLoS One. 2010;5(7):e11866. PubMed.

    . Generation of an apoptotic intracellular peptide by gamma-secretase cleavage of Alzheimer's amyloid beta protein precursor. J Alzheimers Dis. 2000 Nov;2(3-4):289-301. PubMed.

    . Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci. 2009 Oct 15;122(Pt 20):3703-14. PubMed.

    . The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase-dependent pathway. J Biol Chem. 2010 Dec 31;285(53):41443-54. PubMed.

    . Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production. J Biol Chem. 2010 Oct 15;285(42):32549-56. PubMed.

    . APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PubMed.

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