Spastic paraplegia preceding PSEN1-related familial Alzheimer's disease.

Introduction: We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 (PSEN1) related familial Alzheimer's disease (AD). Methods: We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP-related genes. Where PSEN1 mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured in vivo the stability of PSEN1 mutant γ-secretase. Results: We identified a PSEN1 variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro PSEN1 revealed that although the mutation does not alter active γ-secretase reconstitution, it destabilizes γ-secretase-amyloid precursor protein (APP)/amyloid beta (Aβn) interactions during proteolysis, enhancing the production of longer Aβ peptides. We then extended our analysis to all 226 PSEN1 pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that PSEN1 cases manifesting initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid-ring arteries, and severe CAA. Discussion: We show that pure SP can precede dementia onset in PSEN1-related familial AD. We recommend PSEN1 genetic testing in patients presenting with SP with no variants in known HSP-related genes, particularly when associated with a family history of cognitive decline

Curious Variables Experiment (CURVE). Variable properties of the dwarf nova SS UMi

We report on extensive photometry of the dwarf nova SS Ursae Minoris throughout nine months of 2004. In total, we recorded two superoutbursts and 11 normal outbursts of the star. SS UMi has been known to show frequent superoutbursts with a mean interval of 84.7 days. Our data suggest that the interval between successive superoutbursts lengthened to 197 days, indicating that SS UMi entered a period of untypical behavior manifested by a growth in the quiescent magnitude of the star and a series of frequent, low-amplitude, normal outbursts observed from July to September 2004. The mean superhump period derived for the April 2004 superoutburst of SS UMi is 0.070149(16) days (101.015 min). Combining this value with an earlier orbital period determination, we were able to derive the period excess, which is equal to 3.5 +/- 1.6%, and estimate the mass ratio of the binary system as equal to q=0.16 +/- 0.07. During the entire superoutburst, the period decreased at a rate of $\dot P/P_{\rm sh} = -6.3(1.4) \times 10^{-5}$. However, detailed analysis of the timings of superhump maxima seem to suggest a more complex period change, with a decrease in the period during the first and last stages of the superoutburst but an increase in the middle interval.Comment: 9 pages, 8 figures, in print in Astronomy & Astrophysic

Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration

Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions

Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aβ. In contrast, E-Aβn stabilizers increase γ-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Aβ production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of γ-secretase/substrate stabilizing compounds for the prevention of AD

Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds.

Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete digestion of long Aβ peptides and enhances the production of Aβ43, which has been shown to be potently amyloidogenic and neurotoxic in vivo

Sample preparation and characterization of artificially aged aircraft coatings for microstructural analysis

The paper describes a method for metallographic preparation of artificially aged aircraft coatings. In order to better understand the in-service performance and identify degradation mechanisms of an aircraft coating, complete characterization of the microstructure is essential. This paper discusses metallographic sample preparation and subsequent microscopy techniques (light optical microscopy, scanning electron microscopy) for characterization of a standard polyurethane aircraft coating system. The preparation method has proven to produce good, consistent results on a wide range of laboratory-produced simulated environmental exposures. The military specification coating system under study (MIL-PRF-85285C and MIL-PRF-23377G) degrades severely after accelerated weathering. Typical degradation includes deterioration of the polyurethane-based resin system in the topcoat and is observed as a visible change in the color. Increased porosity and some physical deterioration were also observed. In addition, some inorganic pigments in the primer appear to migrate into the topcoat during simulated exposure

The effect of calpastatin polymorphism and its interaction with RYR1 genotypes on carcass and meat quality of crossbred pigs

The aim of the study was to establish the relationship between a calpastatin gene (CAST) polymorphism, the ryanodine receptor gene (RYR1) polymorphism and carcass/meat quality traits in crossbred pigs. No significant differences in the analyzed pigs were found between genotypes CC and CT at the locus RYR1 and CD and DD at the locus CAST/MspI in terms of carcass and meat quality. However, a significant association of the CAST/ApaLI polymorphism with carcass quality and meat marbling were observed. The carcasses of AB pigs had significantly higher carcass percentage of lean meat, thinner backfat and thicker muscle, as well as lower meat marbling, as compared with the BB pigs. Furthermore, interactions CAST/MspI × RYR1 and CAST/ApaLI × RYR1 were found significant in relation to all the studied carcass traits. The results presented here imply that the CAST gene recognized with ApaLI may be considered as important in terms of the way it affects porcine carcass quality traits. Moreover, the research has revealed a relationship between CAST and RYR1 genotypes as regards formation of carcass traits in pigs. Follow-up studies, however, should be carried out on larger populations representing all possible CAST genotypes.