Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease

Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Abeta42; encoded by APP), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1-lod support interval for linkage. Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD. To pursue these associations, we analyzed the same haplotypes for association with plasma Abeta42 in 24 extended LOAD families and for association with LOAD in two independent case-control series. One series (MCR, 188 age-matched case-control pairs) did not show association (p=0.64) with the six haplotypes in the 276-kb region spanning three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The other series (MCJ, 109 age-matched case-control pairs) showed significant (p=0.003) association with these haplotypes. In the MCJ series, the H4 (odds ratio [OR]=5.1, p=0.003) and H2(H7) haplotypes (OR=0.60, p=0.04) had the same effects previously reported. In this series, the H8 haplotype (OR=2.7, p=0.098) also had an effect similar as in one previous case control series but not in others. In the extended families, the H8 haplotype was associated with significantly elevated plasma Abeta42 (p=0.02). In addition, the H5(H10) haplotype, which is associated with reduced risk for AD in the other study is associated with reduced plasma Abeta42 (p=0.007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD.     

Genetic variation in a haplotype block spanning IDE influences Alzheimer disease

Linkage studies have identified a large (>60-Mb) region on chromosome 10q that segregates with Alzheimer Disease (AD). Within the region, the gene for insulin degrading enzyme (IDE) represents a notable biological candidate given that it degrades amyloid beta-protein (one of the major constituents of senile plaques) and the intracellular amyloid precursor protein (APP) domain released by gamma-secretase processing. We have used a single nucleotide polymorphism (SNP) genetic association strategy to investigate AD in relation to a 480-kb region encompassing IDE. A 276-kb linkage disequilibrium block was revealed that spans three genes (IDE, KNSL1, and HHEX). Assessing this block in several independent sets of case-control materials (early- and late-onset AD) and focusing also upon quantitative measures that are pertinent to AD diagnosis and severity (MMSE scores, microtubule-associated protein Tau [MAPT] levels in CSF, degree of brain pathology, and age-at-onset) produced extensive evidence for significant AD association. Signals (p-values ranging from 0.05 to <1x10(-9)) were generally stronger when examining haplotypes rather than individual SNPs, and quantitative trait tests most uniformly revealed the detected associations. Consistent risk alleles and haplotypes were apparent across the study, with effects in some cases as large as that of the epsilon4 allele of APOE. A subsequent mutation screen of exons in all three suspect genes provided no evidence for common causative mutations. These results provide substantial evidence that genetic variation within or extremely close to IDE impacts both disease risk and traits related to the severity of AD.     

Insulin deprivation decreases insulin degrading enzyme levels in primary cultured cortical neurons and in the cerebral cortex of rats with streptozotocin-induced diabetes

Background

Many studies have indicated a relationship between diabetes and Alzheimer’s disease (AD). However, the molecular mechanism underlying this association has not been clarified. Among several factors, insulin degrading enzyme (IDE), which plays roles in the degradation of both insulin and amyloid β (Aβ), has gained interest as a potential target in efforts to solve this puzzle. This study sought to examine the effects of varying insulin and/or glucose concentrations on IDE expression.

Latent role of in vitro Pb exposure in blocking Aβ clearance and triggering epigenetic modifications

Both β-amyloid (Aβ) catabolism and epigenetic regulation play critical roles in the onset of neurodegeneration. The latter also contribute to Pb neurotoxicity. The present study explored the role of epigenetic modifiers and Aβ degradation enzymes in Pb-induced latent effects on Aβ overproduction in vitro. Our results indicated that in SH-SY5Y cells exposed to Pb, the expression of NEP and IDE remained declined during the recovery period, accompanied with abnormal increase of Aβ_1-42 and amyloid oligomer. A disruption of selective global post-translational histone modifiers including the decrease of H3K9ac and H4K12ac and the induction of H3K9me2 and H3K27me2 dose dependently was also showed in recovery cells. Moreover, histone deacetylase inhibitor VPA could attenuate latent Aβ accumulation and HDAC activity induced by Pb, which might be by regulating the expression of NEP and IDE epigenetically. Overall, our results suggest sustained reduction of NEP and IDE expression in response to Pb sensitizes recovery SH-SY5Y cells to Aβ accumulation; however, administration of VPA is demonstrated to be beneficial in modulating Aβ clearance.     

Effect of Tong Luo Jiu Nao on Aβ-degrading enzymes in AD rat brains

Ethnopharmacological relevance

Tong Luo Jiu Nao (TLJN) is a modern Chinese formula based on Traditional Chinese Medicine theory that has been used to treat ischemic cerebral stroke and vascular dementia. TLJN belongs to the ethnopharmacological family of medicines. In this study, we investigated the mechanism of the TLJN effect on Alzheimer's disease (AD).

Aim of the study

To investigate the effect of TLJN on β-amyloid-degrading enzymes and learning and memory in the AD rat brain.

Materials and methods

AD rats whose disease was induced by Aβ_25-35 injection into the bilateral hippocampus CA1 region were subjected to intragastric administration of various preparations. The experimental animals were healthy male Sprague-Dawley rats which were randomly divided into normal, sham, model, TLJN min, TLJN max and donepezil hydrochloride groups. Spontaneous alternation and passive avoidance behavior, which are regarded as measures of spatial learning and memory, were investigated using Y-maze testing. Western blotting and immunohistochemistry were used to observe the therapeutic effect of TLJN on the deposits of amyloid plaque and on the expression of synaptophysin, insulin-degrading enzyme and neprilysin.

Results

Y-maze results showed that the AD model group presented with spatial learning and memory impairments. Hematoxylin-eosin and Congo red staining indicated neuronal impairment and deposits of amyloid plaque in the model group and these results were consistent with their learning and memory deficits in the Y-maze. The TLJN-treated groups exhibited prolonged a cavity delitescence, decreased arm entries and improvement in learning and memory. Moreover, the structure of the neurons of the treated groups was restored and the expression of synaptophysin increased in both the hippocampus and cortex. In addition, their levels of insulin-degrading enzyme and neprilysin in the cortex and hippocampus were upregulated and the amyloid plaque was decreased.

Conclusion

TLJN can improve learning and memory, up-regulate insulin-degrading enzyme and neprilysin levels, promote the degrading of Aβ and clear amyloid plaque from the AD rat brain. In future, TLJN may have significant therapeutic potential in the treatment of AD patients.     

Dental epithelial histo-morphogenesis in the mouse: positional information versus cell history

Reciprocal epithelial-mesenchymal interactions control odontogenesis and the cap stage tooth germ mesenchyme specifies crown morphogenesis. The aim of this work was to determine whether this mesenchyme could also control epithelial histogenesis. Dental mesenchyme and enamel organ were dissociated from mouse first lower molars at E14. At this early cap stage, the enamel organ consists of four cell types forming the inner dental epithelium (IDE), primary enamel knot (PEK), outer dental epithelium (ODE) and the stellate reticulum (SR). Pelleted trypsin-dissociated single dental epithelial cells, which had lost all positional information, were reassociated to either dental mesenchyme or dissociated mesenchymal cells and cultured in vitro. Although with different timings, teeth developed in both types of experiments showing a characteristic dental epithelial histogenesis, cusp formation, and the differentiation of functional odontoblasts and ameloblasts. The rapid progression of the initial steps of histogenesis suggested that the cell history was not memorized. The dental mesenchyme, as well as dissociated mesenchymal cells, induced the formation of a PEK indicating that no specific organisation in the mesenchyme is required for this step. However, the proportion of well-formed multicusped teeth was much higher when intact mesenchyme was used instead of dissociated mesenchymal cells. The mesenchymal cell dissociation had consequences for the functionality of the newly-formed PEK.     

One-Year Analysis of the Prospective Multicenter SENTRY Clinical Trial: Safety and Effectiveness of the Novate Sentry Bioconvertible Inferior Vena Cava Filter

Purpose

To prospectively assess the Sentry bioconvertible inferior vena cava (IVC) filter in patients requiring temporary protection against pulmonary embolism (PE).

Endovascular repair of thoracoabdominal aortic aneurysms using fenestrated and branched endografts

Purpose

The study purpose was to review the outcomes of patients treated for thoracoabdominal aortic aneurysms using endovascular repair with fenestrated and branched stent-grafts in a single center.

Novel insights for the treatment of Alzheimer's disease

The development of treatments for Alzheimer's disease (AD) is currently shifting away from the correction of neurotransmitter abnormalities and from attempts to remove the pathognomonic protein deposits. Drug discovery is heading towards novel types of pharmacological interventions which are aimed at more central and upstream pathophysiological events. The large number of upcoming treatment targets can be grouped into two major categories. The first category consists of antecedents of beta amyloid peptide (Aβ) and TAU deposition including Aβ production, degradation and clearance, TAU hyperphosphorylation and aggregation. The second consists of protectors against neuronal dysfunction and premature death such as mitochondrial functioning, nerve growth and regeneration, and neuronal membrane integrity. It is hoped that some of these strategies will not only have larger symptomatic effects than the currently available drugs but also an impact on the underlying neurodegeneration. Since the novel treatments will be typically administered over years they must meet high standards of safety, drug-drug compatibility, and tolerability. Probably the most important target groups for novel treatments are carriers of mutations causing AD, and individuals with minor cognitive impairment representing a pre-dementia stage of the disease. To minimise incorrect case identifications, drug development must be paralleled by improved diagnostic techniques. Novel pharmacological strategies may be cost-effective if disability and need of full-time care can be postponed or prevented without prolonging time lived with dementia or extending survival. We are uncertain whether the advent of novel disease-retarding strategies will revolutionise the management of AD. Symptomatic treatments will continue to be needed, and psychosocial approaches will retain an essential role in supporting affected individuals and their families.