Brain amyloid β protein and memory disruption in Alzheimer’s disease

The development of amyloid-containing neuritic plaques is an invariable characteristic of Alzheimer’s diseases (AD). The conversion from monomeric amyloid β protein (Aβ) to oligomeric Aβ and finally neuritic plaques is highly dynamic. The specific Aβ species that is correlated with disease severity remains to be discovered. Oligomeric Aβ has been detected in cultured cells, rodent and human brains, as well as human cerebrospinal fluid. Synthetic, cell, and brain derived Aβ oligomers have been found to inhibit hippocampal long-term potentiation (LTP) and this effect can be suppressed by the blockage of Aβ oligomer formation. A large body of evidence suggests that Aβ oligomers inhibit N-methyl-D-aspartate receptor dependent LTP; additional receptors have also been found to elicit downstream pathways upon binding to Aβ oligomers. Amyloid antibodies and small molecular compounds that reduce brain Aβ levels and block Aβ oligomer formation are capable of reversing synaptic dysfunction and these approaches hold a promising therapeutic potential to rescue memory disruption

Potential of Tocotrienols in the Prevention and Therapy of Alzheimer’s Disease

Currently there is no cure for Alzheimer’s disease (AD); clinical trials are underway to reduce amyloid generation and deposition, a neuropathological hallmark in brains of AD patients. While genetic factors and neuroinflammation contribute significantly to AD pathogenesis, whether increased cholesterol level is a causative factor or a result of AD is equivocal. Prenylation of proteins regulating neuronal functions requires mevalonate-derived farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The observation that the levels of FPP and GGPP, but not that of cholesterol, are elevated in AD patients is consistent with the finding that statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, reduce FPP and GGPP levels and amyloid β protein production in preclinical studies. Retrospective studies show inverse correlations between incidence of AD and the intake and serum levels of the HMG CoA reductase-suppressive tocotrienols; tocopherols show mixed results. Tocotrienols, but not tocopherols, block the processing and nuclear localization of sterol regulatory element binding protein-2, the transcriptional factor for HMG CoA reductase and FPP synthase, and enhance the degradation of HMG CoA reductase. Consequently, tocotrienols deplete the pool of FPP and GGPP and potentially blunt prenylationdependent AD pathogenesis. The anti-inflammatory activity of tocotrienols further contributes to their protection against AD. The mevalonate- and inflammation- suppressive activities of tocotrienols may represent those of an estimated 23,000 mevalonate-derived plant secondary metabolites called isoprenoids, many of which are neuroprotective. Tocotrienol-containing plant foods and tocotrienol derivatives and formulations with enhanced bioavailability may offer a novel approach in AD prevention and treatment

Peripheral blood mononuclear cell-converted induced pluripotent stem cells (iPSCs) from an early onset Alzheimer's patient

AbstractImprovement in transduction efficiency makes it possible to convert blood cells into induced pluripotent stem cells (iPSC). In this study, we generated an iPSC line from peripheral blood mononuclear cells (PBMC) donated by a patient who exhibited memory deficit at age 59; outcome of positron emission tomography scan is consistent with a diagnosis of Alzheimer's disease. Integration-free CytoTune-iPS Sendai Reprogramming factors which include Sendai virus particles of the four Yamanaka factors Oct4, Sox2, Klf4, and c-Myc were introduced to PBMC to convert them to iPSCs without retention of virus. Three germ layer differentiation was induced to demonstrate the pluripotency of these iPSCs

Hidden Path Selection Network for Semantic Segmentation of Remote Sensing Images

Targeting at depicting land covers with pixel-wise semantic categories, semantic segmentation in remote sensing images needs to portray diverse distributions over vast geographical locations, which is difficult to be achieved by the homogeneous pixel-wise forward paths in the architectures of existing deep models. Although several algorithms have been designed to select pixel-wise adaptive forward paths for natural image analysis, it still lacks theoretical supports on how to obtain optimal selections. In this paper, we provide mathematical analyses in terms of the parameter optimization, which guides us to design a method called Hidden Path Selection Network (HPS-Net). With the help of hidden variables derived from an extra mini-branch, HPS-Net is able to tackle the inherent problem about inaccessible global optimums by adjusting the direct relationships between feature maps and pixel-wise path selections in existing algorithms, which we call hidden path selection. For the better training and evaluation, we further refine and expand the 5-class Gaofen Image Dataset (GID-5) to a new one with 15 land-cover categories, i.e., GID-15. The experimental results on both GID-5 and GID-15 demonstrate that the proposed modules can stably improve the performance of different deep structures, which validates the proposed mathematical analyses

Dissembled DJ-1 high molecular weight complex in cortex mitochondria from Parkinson's disease patients

The PARK7 gene encodes a protein, DJ-1, with several functions such as protection of cells from oxidative stress, sperm maturation and fertilization, and chaperone activity. Mutations in the PARK7 gene are associated with autosomal recessive early-onset Parkinson's disease (PD). DJ-1 has been reported to be expressed in multiple cells in the central nerve system. Here, by using both native and denatured Western blots, we examined levels of total DJ-1 and high molecular weight complexes of DJ-1 (HMW) in both the substantia nigra and cortex from rapidly autopsied 18 PD and 9 non-pathological control (NPC) brains. We have discovered that the level of total DJ-1 protein is significantly reduced in the substantia nigra in brains of sporadic PD patients. Moreover, in the PD cortex mitochondria fraction, the HMW DJ-1 complex is significantly lower than in the NPC. These results suggest abnormal DJ-1 expression levels and DJ-1 complex changes may contribute to PD pathogenesis

Chronic treatment with anesthetic propofol attenuates β-amyloid protein levels in brain tissues of aged mice

Alzheimer’s disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of β-amyloid protein (Aβ) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Aβ levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Aβ (Aβ40 and Aβ42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of β-site amyloid precursor protein cleaving enzyme (the enzyme for Aβ generation), and increased the levels of neprilysin (the enzyme for Aβ degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Aβ levels potentially via decreasing brain levels of β-site amyloid precursor protein cleaving enzyme, thus decreasing Aβ generation; and via increasing brain neprilysin levels, thus increasing Aβ degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research

Phenotypic analysis of images of zebrafish treated with Alzheimer's γ-secretase inhibitors

<p>Abstract</p> <p>Background</p> <p>Several γ-secretase inhibitors (GSI) are in clinical trials for the treatment of Alzheimer's disease (AD). This enzyme mediates the proteolytic cleavage of amyloid precursor protein (APP) to generate amyloid β protein, Aβ, the pathogenic protein in AD. The γ-secretase also cleaves Notch to generate Notch Intracellular domain (NICD), the signaling molecule that is implicated in tumorigenesis.</p> <p>Results</p> <p>We have developed a method to examine live zebrafish that were each treated with γ-secretase inhibitors (GSI), DAPT {N- [N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine <it>t</it>-Butyl Ester}, Gleevec, or fragments of Gleevec. These compounds were first tested in a cell-based assay and the effective concentrations of these compounds that blocked Aβ generation were quantitated. The mortality of zebrafish, as a result of exposure to different doses of compound, was assessed, and any apoptotic processes were examined by TUNEL staining. We then used conventional and automatic microscopes to acquire images of zebrafish and applied algorithms to automate image composition and processing. Zebrafish were treated in 96- or 384-well plates, and the phenotypes were analyzed at 2, 3 and 5 days post fertilization (dpf). We identified that AD95, a fragment of Gleevec, effectively blocks Aβ production and causes specific phenotypes that were different from those treated with DAPT. Finally, we validated the specificity of two Notch phenotypes (pigmentation and the curvature of tail/trunk) induced by DAPT in a dose-dependent manner. These phenotypes were examined in embryos treated with GSIs or AD95 at increasing concentrations. The expression levels of Notch target gene <it>her6 </it>were also measured by <it>in situ </it>hybridization and the co-relationship between the levels of Notch inhibition by DAPT and AD95 and the severity of phenotypes were determined.</p> <p>Conclusion</p> <p>The results reported here of the effects on zebrafish suggest that this newly developed method may be used to screen novel GSIs and other leads for a variety of therapeutic indications.</p

Conservation of Carbohydrate Binding Interfaces — Evidence of Human HBGA Selection in Norovirus Evolution

Human noroviruses are the major viral pathogens of epidemic acute gastroenteritis. These genetically diverse viruses comprise two major genogroups (GI and GII) and approximately 30 genotypes. Noroviruses recognize human histo-blood group antigens (HBGAs) in a diverse, strain-specific manner. Recently the crystal structures of the HBGA-binding interfaces of the GI Norwalk virus and the GII VA387 have been determined, which allows us to examine the genetic and structural relationships of the HBGA-binding interfaces of noroviruses with variable HBGA-binding patterns. Our hypothesis is that, if HBGAs are the viral receptors necessary for norovirus infection and spread, their binding interfaces should be under a selection pressure in the evolution of noroviruses.Structural comparison of the HBGA-binding interfaces of the two noroviruses has revealed shared features but significant differences in the location, sequence composition, and HBGA-binding modes. On the other hand, the primary sequences of the HBGA-binding interfaces are highly conserved among strains within each genogroup. The roles of critical residues within the binding sites have been verified by site-directed mutagenesis followed by functional analysis of strains with variable HBGA-binding patterns.Our data indicate that the human HBGAs are an important factor in norovirus evolution. Each of the two major genogroups represents an evolutionary lineage characterized by distinct genetic traits. Functional convergence of strains with the same HBGA targets subsequently resulted in acquisition of analogous HBGA binding interfaces in the two genogroups that share an overall structural similarity, despite their distinct locations and amino acid compositions. On the other hand, divergent evolution may have contributed to the observed overall differences between and within the two lineages. Thus, both divergent and convergent evolution, as well as the polymorphic human HBGAs, likely contribute to the diversity of noroviruses. The finding of genogroup-specific conservation of HBGA binding interfaces will facilitate the development of rational strategies to control and prevent norovirus-associated gastroenteritis