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From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

ABSTRACT: Successive oxidative stress and biochemical changes results in neuronal death and neuritic plaques growth in Alzheimer's disease (AD). Therefore, it is interest to analyze amyloid-?eta precursor protein (APP), beta-secretase 1 (BACE1), presenilin (PSEN1 and PSEN2) genes from brain tissues to gain insights. Development of potential inhibitors for these targets is of significance. EST sequences of 2898 (APP), 539 (BACE1), 786 (PSEN1) and 314 (PSEN2) genes were analyzed in this study. A contig sequences with APP (contigs 1-4), BACE1 (contigs 5-7), PSEN1 (contigs 8, 9, 10, 11), PSEN2 (contigs 13, 14) except PSEN1 (contigs 10) and PSEN2 (contigs 13) genes were identified. APP (contig 3 without translational error) was further analyzed using molecular modeling and docking to show its binding with curcumin (principal curcuminoid of turmeric) having -7.3 kcal/mol interaction energy for further consideration as a potential inhibitor.

SUBMITTER: Aathi M

PROVIDER: S-EPMC6900319 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

Aathi Muthusankar M Piramanayagam Shanmughavel S

Bioinformation 20191031 10

Successive oxidative stress and biochemical changes results in neuronal death and neuritic plaques growth in Alzheimer's disease (AD). Therefore, it is interest to analyze amyloid-βeta precursor protein (APP), beta-secretase 1 (BACE1), presenilin (PSEN1 and PSEN2) genes from brain tissues to gain insights. Development of potential inhibitors for these targets is of significance. EST sequences of 2898 (APP), 539 (BACE1), 786 (PSEN1) and 314 (PSEN2) genes were analyzed in this study. A contig sequ ...[more]

PMID: 31831959

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Project description:BackgroundAlzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1-43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1-42. However, a direct effect on Aβ1-43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.MethodsN = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1-43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1-42 and Aβ1-40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.ResultsA known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1-43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1-43 levels positively correlated with CSF Aβ1-42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1-43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1-43 and Aβ1-42 levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations.ConclusionThis is the first time that Aβ1-43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1-43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1-43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.

Project description:BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Project description:BackgroundStudies in animal models of Alzheimer's disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction. Whether and how AD-related neurophysiological alterations translate between mice and humans remains however uncertain.MethodsWe characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early pre-symptomatic changes. Longitudinal local field potential recordings were performed in APP/PS1 mice and cross-sectional magnetoencephalography recordings in human APP and/or PSEN1 mutation carriers. All recordings were acquired in the left frontal cortex, parietal cortex, and hippocampus. Spectral power and functional connectivity were analyzed and compared with wildtype control mice and healthy age-matched human subjects.ResultsAPP/PS1 mice showed increased absolute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 moa. Relative power showed an overall shift from lower to higher frequencies over almost the entire recording period and across all three brain regions. Human mutation carriers, on the other hand, did not show changes in power except for an increase in relative theta power in the hippocampus. Mouse parietal cortex and hippocampal power spectra showed a characteristic peak at around 8 Hz which was not significantly altered in transgenic mice. Human power spectra showed a characteristic peak at around 9 Hz, the frequency of which was significantly reduced in mutation carriers. Significant alterations in functional connectivity were detected in theta, alpha, beta, and gamma frequency bands, but the exact frequency range and direction of change differed for APP/PS1 mice and human mutation carriers.ConclusionsBoth mice and humans carrying APP and/or PSEN1 mutations show abnormal neurophysiological activity, but several measures do not translate one-to-one between species. Alterations in absolute and relative power in mice should be interpreted with care and may be due to overexpression of amyloid in combination with the absence of tau pathology and cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models, for instance, those also including tau pathology, provide better translation to the human AD continuum.

Dataset Information

From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

Publications

From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

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