Bolkan BJ, Triphan T, Kretzschmar D.
β-secretase cleavage of the fly amyloid precursor protein is required for glial survival.
J Neurosci. 2012 Nov 14;32(46):16181-92.
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This is an interesting report detailing the requirement of BACE1 cleavage of fly amyloid precursor protein (APP) for glial survival. The authors have nicely demonstrated their thesis using three key approaches: β-site APP cleaving enzyme 1 (BACE1) deficiency, APP knockout rescue, and secretion-deficient APP mutant enhancement of phenotype. The results are solid and the conclusions well supported. The definitive nature of the results using this model system is a testament to the power of fly genetics.
A central question that emerges from this work is whether the authors’ results in the Drosophila system might translate to mammals. In this regard, it is unclear what the mammalian glial homologue to fly glia is. Also, it should be noted that both the APP and BACE1 knockout mice have non-lethal and, it could be said, even relatively weak phenotypes. For example, the first report detailing APP-deficient mice found shorter neuronal processes and gliosis associated with reduced locomotor activity (Zheng et al., 1995). BACE1 knockouts are healthy, with only minor defects in behavior and delayed myelination (Roberds et al., 2001; Cai et al., 2001; Luo et al., 2001). The most parsimonious explanation for these discrepancies is the multiple levels of redundancy present in mammals. As an example, mammals have APP-like proteins in addition to APP, and also express BACE2.
Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC.
BACE1 is the major beta-secretase for generation of Abeta peptides by neurons.
Nat Neurosci. 2001 Mar;4(3):233-4.
Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R.
Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation.
Nat Neurosci. 2001 Mar;4(3):231-2.
Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L.
BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.
Hum Mol Genet. 2001 Jun 1;10(12):1317-24.
Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, Heavens RP, Dawson GR, Boyce S, Conner MW, Stevens KA, Slunt HH, Sisoda SS, Chen HY, Van der Ploeg LH.
beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity.
Cell. 1995 May 19;81(4):525-31.