Mutations of beta-amyloid precursor protein alter the consequence of Alzheimer's disease pathogenesis

Alzheimer's disease is pathologically defined by accumulation of extracellular amyloid-β(Aβ). Approximately 25 mutations in β-amyloid precursor protein(APP) are pathogenic and cause autosomal dominant Alzheimer's disease. To date, the mechanism underlying the effect of APP mutation on Aβ generation is unclear. Therefore, investigating the mechanism of APP mutation on Alzheimer's disease may help understanding of disease pathogenesis. Thus, APP mutations(A673T, A673 V, E682 K, E693 G, and E693Q) were transiently co-transfected into human embryonic kidney cells. Western blot assay was used to detect expression levels of APP, beta-secretase 1, and presenilin 1 in cells. Enzyme-linked immunosorbent assay was performed to determine Aβ_(1–40) and Aβ_(1–42) levels. Liquid chromatography-tandem mass chromatography was used to examine VVIAT, FLF, ITL, VIV, IAT, VIT, TVI, and VVIA peptide levels. Immunofluorescence staining was performed to measure APP and early endosome antigen 1 immunoreactivity. Our results show that the protective A673 T mutation decreases Aβ_(42)/Aβ_(40) rate by downregulating IAT and upregulating VVIA levels. Pathogenic A673 V, E682 K, and E693 Q mutations promote Aβ_(42)/Aβ_(40) rate by increasing levels of CTF99, Aβ_(42), Aβ_(40), and IAT, and decreasing VVIA levels. Pathogenic E693 G mutation shows no significant change in Aβ_(42)/Aβ_(40) ratio because of inhibition of γ-secretase activity. APP mutations can change location from the cell surface to early endosomes. Our findings confirm that certain APP mutations accelerate Aβ generation by affecting the long Aβ cleavage pathway and increasing Aβ_(42/40) rate, thereby resulting in Alzheimer's disease.

Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging

Interleukin-1βis a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer’s disease,Parkinson’s disease,stroke and persistent pain.Activated microglia are the main cellular source of interleukin-1βin the brain.Cathepsin B is associated with the production and secretion of interleukin-1βthrough pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes.The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A,which can stabilize mitochondrial DNA.Therefore,microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging.Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging.

超塑化剂与水泥流动性能评估

为获得持久的混凝土结构,最重要的一步就是混凝土的无损浇注。在过去的十几年里,混凝土材料间的兼容性是控制无损浇注混凝土的工作性的重要问题,这一课题备受关注。每位工程师都希望有可靠的方法检测超塑化剂与水泥的流动性能。在这篇文章中,我们从基本原理着眼对检测流动性能的方法进行了论述。重要的一点就是超塑性混凝土的变形性质。当新拌混凝土均质性地变形时,混凝土拌和物的工作性可以被超塑化剂的一个基本理论所解释,也就是,流动性与水化物的表面积超塑化剂吸附量成正比关系。而且,超塑化剂与水泥的流动性检测还应考虑水灰比和材料混合程序等混凝土的实际情况。