Alzheimer's disease (AD) is characterized pathologically by cholinergic deficits, extracelluar amyloid deposit, intra-neuronal neurofibrillary tangles, gliosis and neuronal and synaptic loss. The primary therapeutic approach has been cholinergic augumentation by chlolinesterase inhibitors, which at best modestly improve cognitive function. Several recent advances have provided new insights and possibilities in defining therapeutic targets for AD. Research on the underlying pathophysiological dysfunction finally disclose more disease specific processes. Of particular importance is the identification and characterization of the secretases involved in endoproteolytic processing of beta-amyloid precursor protein, the precursor of the amyloid beta-peptide (A beta). It is generally accepted that A beta has pivotal role in the pathogenesis of AD, and that reducing brain A beta levels may be a disease modifying strategy. By inhibiting one or both amyloidogenic secretase and immunization with A beta, neuropathological features of AD can be prevented or alleviated.
Alzheimer Disease* ; Amyloid beta-Peptides ; Amyloid Precursor Protein Secretases ; Brain ; Gliosis ; Immunization ; Neurofibrillary Tangles ; Neurons ; Plaque, Amyloid ; Presenilins

Extracellular accumulation of amyloid beta protein (Abeta) plays a central role in Alzheimer's disease (AD). Some metals, such as copper, lead, and aluminum can affect the Abeta accumulation in the brain. However, the effect of mercury on Abeta accumulation in the brain is not clear. Thus, this study was proposed to estimate whether mercury concentration affects Abeta accumulation in PC12 cells. We treated 10, 100, and 1000 nM HgCl2 (Hg) or CH3HgCl2 (MeHg) for 48 hr in PC12 cells. After treatment, Abeta40 in culture medium increased in a dose- and time-dependent manner. Hg and MeHg increased amyloid precursor protein (APP), which is related to Abeta production. Neprilysin (NEP) levels in PC12 cells were decreased by Hg and MeHg treatment. These results suggested that Hg induced Abeta accumulation through APP overproduction and reduction of NEP.
Aluminum ; Alzheimer Disease ; Amyloid beta-Peptides ; Amyloid Precursor Protein Secretases ; Amyloid* ; Animals ; Brain ; Copper ; Mercuric Chloride ; Metals ; Neprilysin ; PC12 Cells*

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

Increased neuronal apoptosis is an important pathological feature of Alzheimer's disease (AD). The Bcl-2-interacting mediator of cell death (Bim) mediates amyloid-beta (Aβ)-induced neuronal apoptosis. Naturally-occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. In this study, we found that circulating NAbs-Bim were decreased in AD patients. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions. Furthermore, NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβ deposition, tau hyperphosphorylation, microgliosis, and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein. These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.
Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Amyloid beta-Protein Precursor/metabolism* ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic

OBJECTIVE: To compare the clinical efficacy of abdominal acupoint thread embedding therapy based on "brain-intestinal connection" combined with donepezil hydrochloride tablets and oral donepezil hydrochloride tablets alone for mild-to-moderate Alzheimer's disease (AD) and observe its effects on amyloid precursor protein (APP) and β-amyloid protein METHODS: Sixty patients with AD were randomly divided into an observation group (30 cases, 3 cases dropped off) and a control group (30 cases, 3 cases dropped off). The patients in the control group were treated with donepezil hydrochloride tablets (5 mg per day); based on the treatment in the control group, the patients in the observation group were treated with abdominal acupoint thread embedding therapy at Zhongwan (CV 12), Xiawan (CV 10), Huaroumen (ST 24), Wailing (ST 26), Daheng (SP 15), etc., once every 10 days. Both groups were treated for 2 months. The mini-mental state examination (MMSE), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), activity of daily living scale (ADL), neuropsychiatric inventory questionnaire (NPI) as well as the serum levels of APP and Aβ RESULTS: After treatment, the MMSE scores in the two groups were higher than those before treatment ( CONCLUSION The abdominal acupoint thread embedding therapy based on the theory of "brain-intestinal connection" combined with donepezil hydrochloride tablets can improve cognitive function, self-care ability of daily life and mental behavior, and reduce the serum levels of APP and Aβ
Acupuncture Points ; Alzheimer Disease/drug therapy* ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Brain ; Donepezil ; Humans ; Peptide Fragments

Amyloid beta (Aβ) plaques are one of the hallmarks of Alzheimer's disease (AD). However, currently available anti-amyloid therapies fail to show effectiveness in the treatment of AD in humans. It has been found that there are different types of Aβ plaque (diffuse and focal types) in the postmortem human brain. In this study, we aimed to investigate the correlations among different types of Aβ plaque and AD-related neuropathological and cognitive changes based on a postmortem human brain bank in China. The results indicated that focal plaques, but not diffuse plaques, significantly increased with age in the human hippocampus. We also found that the number of focal plaques was positively correlated with the severity of AD-related neuropathological changes (measured by the "ABC" scoring system) and cognitive decline (measured by the Everyday Cognitive Insider Questionnaire). Furthermore, most of the focal plaques were co-localized with neuritic plaques (identified by Bielschowsky silver staining) and accompanied by microglial and other inflammatory cells. Our findings suggest the potential of using focal-type but not general Aβ plaques as biomarkers for the neuropathological evaluation of AD.
Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Amyloid beta-Protein Precursor ; Brain/pathology* ; Cognitive Dysfunction/pathology* ; Hippocampus/metabolism* ; Humans ; Neuroinflammatory Diseases ; Plaque, Amyloid/pathology*

<p>OBJECTIVETo observe the influence of H102 on the expression of amyloid protein and amyloid precursor protein in the hippocampus of APP695 transgenic mice.p><p>METHODSThe 9-month-old APP695 transgenic mice were randomly divided into the model group and the H102 group; C57BL/6J mice were adopted as normal control group. The H102 group were injected with H102 in a dose of 3 microl/per mouse in lateral ventricle, once a day, for ten days; while the model group and the control group were injected with saline. The hippocampus and temporal cortex of the brain sections from transgenic mice and wild type female mice were subjected to immunohistochemistry and Congo red histological staining, and observed the difference of the protein expression under microscope. The expression of the APP protein was detected by Western blot.p><p>RESULTSAbeta and APP immunohistochemistry showed density of positive cell in the CA1 region of hippocampus of control group were less than model group. H102 peptide reduced the area, and density of positive cells. Congo red staining showed there were lots of amyloid plagues in the brains of model mice but not in the brains of normal control. And the Western blot showed the content of the APP protein of the model group was much higher than the H102 group. H102 significantly decreased the amyloid plagues.p><p>CONCLUSIONThe expression of APP, Abeta are increased in APP695 transgenic mice, and H102 can decrease the level of APP, Abeta in transgenic mice.p>
Amyloid beta-Protein Precursor ; metabolism ; Amyloidogenic Proteins ; metabolism ; Animals ; Brain ; metabolism ; Female ; Gene Expression ; Hippocampus ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic

<p>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).p><p>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.p><p>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.p><p>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.p>
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

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

OBJECTIVE: To observe the gait changes of Alzheimer's disease PS1M146V/APPswe/tauP301L triple-transgenic (3xTg-AD) mice and to investigate the improvement effect of single chain variable domain antibody fragment 17 (scFv17) on the gait. METHODS: In the present study, a selection of 6-month-old 3xTg-AD mice (=18) and C57BL/6 wild-type mice (=24) was performed. First, we observed their gait changes and found that the gait of 12-month-old 3xTg-AD mice was severely damaged. Then, the two groups of mice were randomly divided into four groups:WT+PBS(=12), WT+scFv17(=12), 3xTg-AD+PBS(=9) and 3xTg-AD+scFv17(=9). The gait behavior test and pathological test were performed after 12 weeks'continuous administration of scFv17 (1.5 mg/kg) or an equal volume of PBS (0.01 mol/L) by nasal gavage twice a week. RESULTS: Compared with the same month old wild type mice, the rear track width of 12 month old 3xTg-AD mice was increased(<0.01), swing time percent was decreased (<0.01), stance time percent was increased(<0.01), so the ability of movement coordination and balance was seriously damaged. ScFv17 could improve the coordination and balance ability of 12 month old 3xTg-AD mice(<0.01). The morphological structure of 3xTg-AD mice cerebellar Purkinje cells was improved. The treatment of scFv17 increased the Nissl body number of the cerebellar Purkinje cells of 3xTg-AD mice (<0.01). scFv17 reduced the amyloid β protein (Aβ) plaques in the cerebellar cortex of 3xTg-AD mice (<0.01), and scFv17 reduced the intracellular neurofibrillary tangles (NFT) of the cerebellar Purkinje cells of the 3xTg-AD mice (<0.01). CONCLUSIONS The coordination and balance ability of 3xTg-AD mice was significantly impaired. ScFv17 can improve gait behaviour in the 3xTg-AD significantly.The mechanism may be related to the improvement of the structure and protein function of cerebellar Purkinje cells, and the eliminating of the Aβ plaques and the neurofibrillary tangles.
Alzheimer Disease ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Animals ; Disease Models, Animal ; Gait ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; tau Proteins