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[gamma]-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-[beta] precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-[beta] (A[beta]) 40 peptide to greater production of A[beta]42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little A[beta]40 or A[beta]42 production, and FAD PS2 alleles support robust production of only A[beta]42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a 'gained' competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against [gamma]-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct [gamma]-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates. Alzheimer's disease | endoproteolysis | PS1 | PS2 | Notch

A yeast two-hybrid screen is used to identify [Na.sub.v]1.5-associated proteins that might be involved in channel function and expression and also identify [alpha]-actinin-2 as an interacting partner of the cytoplasmic loop connecting domains III and IV of [Na.sub.v]1.5 ([Na.sub.v]1.5/LIII-IV). The obtained data suggested that [alpha]-actinin-2 which is known to mediate the functional expression of the potassium channels might play a role in fixing [Na.sub.v]1.5 to the membrane by connecting the channel to the actin cytoskeleton network.

Multiple lines of evidence suggest that specific subtypes of age-related cataract (ARC) and Alzheimer disease (AD) are related etiologically. To identify shared genetic factors for ARC and AD, we estimated co-heritability of quantitative measures of cataract subtypes with AD-related brain MRI traits among 1,249 members of the Framingham Eye Study who had a brain MRI scan approximately ten years after the eye exam. Cortical cataract (CC) was found to be co-heritable with future development of AD and with several MRI traits, especially temporal horn volume (THV, p = 0.24, P<10-4). A genome-wide association study using 187,657 single nucleotide polymorphisms (SNPs) for the bivariate outcome of CC and THV identified genome-wide significant association with CTNND2 SNPs rs17183619, rs13155993 and rs13170756 (P<2.6x10-7). These SNPs were also significantly associated with bivariate outcomes of CC and scores on several highly heritable neuropsychological tests (5.7x10-9≤P<3.7x10-6). Statistical interaction was demonstrated between rs17183619 and APP SNP rs2096488 on CC (P = 0.0015) and CC-THV (P = 0.038). A rare CTNND2 missense mutation (G810R) 249 base pairs from rs17183619 altered δ-catenin localization and increased secreted amyloid-β1-42 in neuronal cell culture. Immunohistopathological analysis of lens tissue obtained from two autopsy-confirmed AD subjects and two non-AD controls revealed elevated expression of δ-catenin in epithelial and cortical regions of lenses from AD subjects compared to controls. Our findings suggest that genetic variation in delta catenin may underlie both cortical lens opacities in mid-life and subsequent MRI and cognitive changes that presage the development of AD. [ABSTRACT FROM AUTHOR]

&#x03B3-secretase depends on presence of presenilins (PS), Nct, Aph-I, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-β precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PSI or P52 genes shift APP cleavage from production of amyloid-β (Aβ) 40 peptide to greater production of Aβ42. Although studies in PSI/PS2-deficient embryonic cells define overlapping activities for these proteins. in vivo complementation of PSI-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PSI transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Aβ40 or Aβ42 production. and FAD PS2 alleles support robust production of only Aβ42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a "gained" competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against &#x03B3-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct &#x03B3-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates. [ABSTRACT FROM AUTHOR]