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.

Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy

The mechanisms of the transplantation of neural stem cells(NSCs)in the treatment of Alzheimer’s disease remain poorly understood.In this study,NSCs were transplanted into the hippocampal CA1 region of the rTg(tau P301L)4510 mouse model,a tauopathy model that is thought to reflect the tau pathology associated with Alzheimer’s disease.The results revealed that NSC transplantation reduced the abnormal aggregation of tau,resulting in significant improvements in the short-term memory of the tauopathy model mice.Compared with wild-type and phosphate-buffered saline(PBS)-treated mice,mice that received NSC transplantations were characterized by changes in the expression of multiple proteins in brain tissue,particularly those related to the regulation of tau aggregation or misfolding.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis and Gene Ontology(GO)function analysis revealed that these proteins were primarily enriched in pathways associated with long-term potentiation,neurogenesis,and other neurobiological processes.Changes in the expression levels of key proteins were verified by western blot assays.These data provided clues to improve the understanding of the functional capacity associated with NSC transplantation in Alzheimer’s disease treatment.This study was approved by the Beijing Animal Ethics Association and Ethics Committee of Beijing Institute of Technology(approval No.SYXK-BIT-school of life science-2017-M03)in 2017.

Microstructure and properties of aging Cu–Cr–Zr alloy

The crystallography and morphology of precipitate particles in a Cu matrix were studied using an aged Cu–Cr–Zr alloy by transmission electron microscopy（TEM） and high-resolution transmission electron microscopy（HRTEM）. The tensile strength and electrical conductivity of this alloy after various aging processes were tested. The results show that two kinds of crystallographic structure associated with chromium-rich phases, fcc and bcc structure, exist in the peak-aging of the alloy. The orientation relationship between bcc Cr precipitate and the matrix exhibits Nishiyama–Wasserman orientation relationship. Two kinds of Zr-rich phases（Cu4Zr and Cu5Zr）can be identified and the habit plane is parallel to {111}Cu plane during the aging. The increase in strength is ascribed to the precipitation of Cr- and Zr-rich phase.