Amyloid ; Amyloid Neuropathies, Familial/genetics* ; China ; Humans ; Mutation ; Prealbumin/genetics*

Amyloid Neuropathies, Familial/genetics* ; Humans ; Prealbumin/genetics*

The increase in different precursor proteins that have been shown to form amyloid fibrils and the identification of common properties have not yet led to any unifying theory or mechanism for the pathogenesis of amyloidogenesis. Papua New Guinea holds a unique place in the story of amyloidosis and in this article we review the current status of amyloidosis research indicating how this relates to those forms relevant to Papua New Guinea. This review concentrates on secondary reactive amyloid (AA), which is found in the highest frequency in the world in parts of Papua New Guinea, and kuru, in which the amyloid protein itself is infectious. The history, pathogenesis and future prospects for these diseases are discussed in the light of what is known about other forms of amyloidosis
Amyloid beta-Peptides ; Amyloid - genetics ; Global Health ; Humans ; Mutation ; Papua New Guinea - epidemiology ; Serum Amyloid A Protein

Amyloid Neuropathies, Familial ; genetics ; Cardiomyopathies ; Humans ; Mutation

Humans ; Alzheimer Disease/genetics* ; Apolipoprotein E4/genetics* ; Amyloid beta-Peptides

OBJECTIVE: To investigate the effect of osthole on the expression of amyloid precursor protein (APP) in Alzheimer's disease (AD) cell model and its mechanism. METHODS: The SH-SY5Y cell with over expression of APP was established by transfection by liposome 2000. The cells were treated with different concentrations of osthole, and the cell viability was determined by MTT and lactate dehydrogenase (LDH) assay. The differentially expressed miRNAs with and without osthole treatment were detected by miRNA array, and the target genes binding to the differentially expressed miRNAs were identified and verified by databases and Cytoscape. After the inhibitor of the differentially expressed miRNA was transduced into cells, the changes of APP and amyloid β (Aβ) protein were determined by immunofluorescence cytochemistry, and the mRNA expression of APP was determined by RT-PCR. RESULTS: The AD cell model with over expression of APP was established successfully. The results of MTT and LDH assay showed that osthole had a protective effect on cells and alleviated cell damage. miR-101a-3p was identified as the differentially expressed miRNA, which was binding to the 3'-UTR of APP. Compared with APP group, the expression of APP and Aβ protein and APP mRNA increased in the miR-101a-3p inhibitor group (all <0.01), while the expression of APP and Aβ protein and APP mRNA decreased in the cells with osthole treatment (all <0.01). CONCLUSIONS Osthole inhibits the expression of APP by up-regulating miR-101a-3p in AD cell model.
Alzheimer Disease ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; genetics ; Cell Line ; Coumarins ; pharmacology ; Gene Expression Regulation ; drug effects ; genetics ; Humans ; MicroRNAs ; genetics ; metabolism

Alzheimer's disease(AD) patients in China have been surging, and the resultant medical burden and care demand have a huge impact on the development of individuals, families, and the society. The active component compound of Epimedii Folium, Astragali Radix, and Puerariae Lobatae Radix(YHG) can regulate the expression of iron metabolism-related proteins to inhibit brain iron overload and relieve hypofunction of central nervous system in AD patients. Hepcidin is an important target regulating iron metabolism. This study investigated the effect of YHG on the expression of a disintegrin and metalloprotease-17(ADAM17), a key enzyme in the hydrolysis of β amyloid precursor protein(APP) in HT22 cells, by mediating hepcidin. To be specific, HT22 cells were cultured in vitro, followed by liposome-mediated siRNA transfection to silence the expression of hepcidin. Real-time PCR and Western blot were performed to examine the silencing result and the effect of YHG on hepcidin in AD cell model. HT22 cells were randomized into 7 groups: control group, Aβ25-35 induction(Aβ) group, hepcidin-siRNA(siRNA) group, Aβ25-35 + hepcidin-siRNA(Aβ + siRNA) group, Aβ25-35+YHG(Aβ+YHG) group, hepcidin-siRNA+YHG(siRNA+YHG) group, Aβ25-35+hepcidin-siRNA+YHG(Aβ+siRNA+YHG) group. The expression of ADAM17 mRNA in cells was detected by real-time PCR, and the expression of ADAM17 protein by immunofluorescence and Western blot. Immunofluorescence showed that the ADAM17 protein expression was lower in the Aβ group, siRNA group, and Aβ+siRNA group than in the control group(P<0.05) and the expression was lower in the Aβ+siRNA group(P<0.05) and higher in the Aβ+YHG group(P<0.05) than in the Aβ group. Moreover, the ADAM17 protein expression was lower in the Aβ+siRNA group(P<0.05) and higher in the siRNA+YHG group(P< 0.05) than in the siRNA group. The expression was higher in the Aβ+siRNA+YHG group than in the Aβ+siRNA group(P<0.05). The results of Western blot and real-time PCR were consistent with those of immunofluorescence. The experiment showed that YHG induced hepcidin to up-regulate the expression of ADAM17 in AD cell model and promote the activation of non-starch metabolic pathways, which might be the internal mechanism of YHG in preventing and treating AD.
ADAM17 Protein ; Alzheimer Disease/genetics* ; Amyloid beta-Peptides ; Drugs, Chinese Herbal/pharmacology* ; Hepcidins/genetics* ; Humans ; Pueraria

OBJECTIVETo study the role of presenilin1 (PS1) in the processing of beta-amyloid precursor protein (APP) to amyloid beta-peptide (Abeta) and its relation to gamma-secretase in the pathogenesis of Alzheimer's disease (AD).

METHODSSeveral CHO cell lines stably transfected with either wide-type or mutant PS1 (M(146)L) along with APP(751) genes were established. The expression of PS1 and its half-life were determined by immunoprecipitation, Western blotting and pulse-chase experiment. Abeta released into the conditional media was quantitated by ELISA.

RESULTSPS1 transfected CHO cells expressed an expected 45,000 full length protein. This over-expressed full length PS1 was subject to fast degradation with a half-life of less than 1 hour. In contrast to full length PS1, the truncated N-terminal and C-terminal proteins of PS1 were significantly more stable with a longer half-life of nearly 16 hours. Although the total amount of Abeta released into the conditional media did not show a significant difference between wild-type and mutant PS1 (M(146)L) transfected APP cells, mutant PS1 (M(146)L) transfected APP cells increase Abeta(1 - 42) (a subspecies of total Abeta) production with nearly a 2 fold increase, comparing to untransfected or wild-type PS1 transfected APP cells.

CONCLUSIONPS1 is involved in the processing of APP to Abeta, a nearly 2 fold increase of Abeta production in mutant PS1 (M(146)L) transfected APP cells indicates that PS1 may be the expected gamma-secretase itself.

Alzheimer Disease ; etiology ; metabolism ; Amyloid Precursor Protein Secretases ; genetics ; metabolism ; Amyloid beta-Peptides ; metabolism ; Amyloid beta-Protein Precursor ; genetics ; Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Mutation ; Peptide Fragments ; metabolism ; Presenilin-1 ; genetics ; metabolism ; Transfection

OBJECTIVETo study the protective effects of astragaloside (AST) on memory impairment and the expression levels of amyloid precursor protein (APP) and its mRNA, alpha secretase and beta secretase mRNA in the brain of mice induced by dexamethasone (DEX).

METHODMice were randomly divided into six groups: control group, model group, AST ( 10, 20, 40 mg x kg(-1)) groups and ginsenoside Rg1 (6.5 mg x kg(-1)) group. The animal models of dysmnesy mice were established by intragastrical administration of DEX (5 mg x kg(-1)) for 21 days. Subsequently, the dysmnesy mice were treated by intragastrical administration of ginsenoside Rg1 and different doses of AST (10, 20, 40 mg x kg(-1)), respectively. Morris water maze was applied to evaluate the learning and memory function in mice. The expression of APP, alpha secretase and beta secretase mRNA were analysed by RT-PCR, and immunohistochemistry was used to evaluate the expression levels of APP in cerebral cortex, hippocampus CA1 and CA3.

RESULTAST (20, 40 mg x kg(-1)) could improve the learning and memory function in mice (P<0.05, P<0.01), decrease the expression levels of APP and beta secretase mRNA (P<0.05), increase the expression level of alpha secretase mRNA (P<0.05), and decrease the expression level of APP in cerebral cortex and hippocampus CA1 (P<0.05).

CONCLUSIONAST could improve the learning and memory function in mice, which mechanism may contribtuted to the expression inhibition of APP and APP mRNA, beta secretase mRNA, and promotion of the expression of alpha secretase mRNA.

Amyloid Precursor Protein Secretases ; genetics ; Amyloid beta-Protein Precursor ; genetics ; Animals ; Dexamethasone ; pharmacology ; Male ; Memory Disorders ; drug therapy ; prevention & control ; Mice ; RNA, Messenger ; analysis ; Saponins ; pharmacology ; Triterpenes ; pharmacology

Adequate assessment of plaque deposition levels in the brain of mouse models of Alzheimer disease (AD) is required in many core issues of studies on AD, including studies on the mechanisms underlying plaque pathogenesis, identification of cellular factors modifying plaque pathology, and developments of anti-AD drugs. The present study was undertaken to quantitatively evaluate plaque deposition patterns in the brains of the two popular AD models, Tg2576 and Tg-APPswe/PS1dE9 mice. Coronally-cut brain sections of Tg2576 and Tg-APPswe/PS1dE9 mice were prepared and plaque depositions were visualized by staining with anti-amyloid beta peptides antibody. Microscopic images of plaque depositions in the prefrontal cortex, parietal cortex, piriform cortex and hippocampus were obtained and the number of plaques in each region was determined by a computer-aided image analysis method. A series of optical images representing a gradual increase of plaque deposition levels were selected in the four different brain regions and were assigned in each with a numerical grade of 1-6, where +1 was lowest and +6, highest, so that plaques per unit in mm2 increased "sigmoidally" over the grading scales. Analyzing plaque depositions using the photographic plaque reference panels and a computer-aid image analysis method, it was demonstrated that the brains of Tg2576 mice started to accumulate predominantly small plaques, while the brains of Tg-APPswe/PS1dE9 mice deposited relatively large plaques.
Alzheimer Disease/genetics/*pathology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Plaque, Amyloid/*pathology