Swedish mutation

Several authors have successfully demonstrated the feasibility of targeting AD genes (e.g., APP-London mutation, APP-Swedish mutation, PSl, APLPl, APLP2, PEN-2, APH-la, Nicastrin, BACE, MAPP-V337M) with RNAi (418-423). Some authors have speculated about the possibility that ABP overproduction might be caused by the loss of epigenetic control in the expression of the genes involved in... 

KM-1 ID1 AEFRHDSG YlEVHHQK16lL VFFAEDVGSNKGMIGLM VGGW44 IA42iTVIVITLVM LK... NL-4 (Swedish mutation)... 

M., Sturchler-Pierrat, C. and Strazielle, C. (2002) Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation. Brain Res 956, 36—44. 

The first reported p-secretase inhibitors, OM991 and OM992 (144) (band 7, Fig. 13.4), were designed by use of the template of the Swedish mutant APP. The Swedish mutation site of /3-secretase action [SEVNL/DAEFR instead of SEVKM/DAEFR wild-type (see Fig. 

The brown algae Ecklonia cava is known for its antioxidant and anti-inflammatory functions. The butanol extract of E. cava reduces Ap secretion from HEK293 cells expressing APP with Swedish mutation and increases soluble APPa and C-terminal fragment-a (CTFa), of which activity is similar to BACE (P-site of APP cleaving enzyme) inhibitors. The extract inhibits Ap oligomerization, particularly midsize oligomer formation, and protects primary cortical neurons from various Ap-induced cell deaths [210]. 

BACE also cleaves at the same location of APP with the so-called Swedish mutation , KM - NL at P2-P1, found in families with early-onset Alzheimer s disease. This indicates that a hydrophobic residue seems to be preferred at the PI position and a hydrophilic residue at P2. One other piece of data was a mutant of the APP substrate of M —> V at position PI, which greatly reduced activity of BACE for the substrate [264, 265]. 

Met (sequence EVKV DA). (C) Swedish mutation substrate with P2-P1 sequence of Asn-Leu (red) in place of wild-type Lys-Met (sequence EVNL DA). (D) Alternative / -secretase cleavage site at APP residue Glu607 (PI ) (sequence DSGY EV). The figure was generated with MOLSCRIPT [287], Raster3D [288], and the GIMP [289]. 

We also modeled the mutant substrate EVKVDA shown in Figure 5.4B. The differences in interaction between the side chain and the enzyme explain why this substrate is cleaved less well by BACE [264]. While the Cyl of Val and Cy of Met are in the same location [xy = —65°), the Cy2 atom of Val contacts the catalytic Asp93 Cr, Oai, and 0 2 atoms. This is likely to interfere with the catalytic activity. Also, many of the hydrophobic contacts between PI Met and the enzyme are missing in PI Val. In Figure 5.4C a model of the Swedish mutation KM —> NL at P2, PI, which is associated with early-onset Alzheimer s disease [269], shows that the Asn can hydrogen bond to... 

Haass, C., Lemere, C.A., CapeU, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L. and Selkoe, D. J. 1995. The Swedish mutation causes early-onset Alzheimer s disease by P-secretase cleavage within the secretory pathway. Nat. Med. 1 1291-1296 Hanger, D.P., Betts, J.C., Loviny, T.L., Blackstock, W.P. and Anderton, B.H. 1998. New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-teM) from Alzheimer s disease brain using nanoelectrospray mass spectrometry. J. Neurochem. 71 2465-2476... 

Gagnon J, Mauriege P, Roy S, Sjo-strom D, Chagnon YC, Dionne FT, Op-pert J-M, Perusse L, Sjostrom L, Bouchard C. The Trp64Arg mutation of the j 3-adrenergic receptor gene has no effect on obesity phenotypes in the Quebec family study and Swedish obese subjects cohorts. J Clin Invest 1996 98 2086-2089. 

Feng, X., Zhao, P., He, Y., Zuo, Z. (2006) AUele-specific silencing of Alzheimer s disease genes the amyloid precursor protein genes with Swedish or London mutations. Gene, 371, 68-74. 

NT097 Jansson, T., L. Romert, J. Magnusson, NT107 and D. Jenssen. Genotoxicity testing of extracts of a Swedish moist oral snuff Mutat Res 1991 261(2) 101-115. 

Folkesson R, MaUdewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, Ganten U, Ganten D, Bader M, Winblad B, Benedikz E (2007) A transgenic rat expressing human APP with the Swedish Alzheimer s disease mutation. Biochem Biophys Res Commun 358 777-782 Foster AC, CoUins JF, Schwarcz R (1983) On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic adds and structurally related compounds. Neuropharmacology 22 1331-1342... 

Mamtle A, Warpman U, Bogdanovic N, Lannfelt L, Nordbetg A (1999) Neuronal nicotinic receptor deficits in Alzheimer patients with the Swedish amyloid precursor protein 670/671 mutation. J Neurochem 72 1161-1169... 

CYP2D6 alleles Functional mutation Consequence Allele frequency (%) Swedish Chinese Zimbabwean ... 

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