Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.
Activities of Daily Living ; Alzheimer Disease/genetics* ; Humans ; Mutation ; Neurodegenerative Diseases ; Presenilin-1/genetics* ; Presenilin-2/genetics*

OBJECTIVETo study the effect of Tiaoxin Recipe (TXR) on learning and memory related gene expression in hippocampus of senescence accelerated mice (SAM).

METHODSChanges of learning and memory related gene expression, including mineralocorticoid receptor (MR), presenile protein 1 and 2 (PS-1, PS-2), tau, APP, apoE and bcl-2 in hippocampus of SAM were determined by reverse transcription polymerase chain reaction (RT-PCR). The effect of TXR were tested. E2020 was used as the drug for control.

RESULTSCompared with those in the same aged mice, in the 5-month old SAM, levels of gene expression of MR, tau, PS-2 and APP were significantly higher, that of apo-E lower, levels of gene expression PS-1 and bcl-2 were unobviously changed; while in the 12-month old SAM, gene expression of MR and tau were higher, bcl-2 was lower and PS-1, PS-2, apoE and APP were also unobviously changed. Continuously orally taken TXR could correct the abnormality of MR, tau and apoE gene expression in hippocampus of 5-month SAM and that of MR and bcl-2 in 12-month SAM.

CONCLUSIONContinuously orally taken of TXR has the effect of regulating and correcting learning and memory related gene expression in hippocampus of 5-month and 12-month SAM.

Aging ; drug effects ; metabolism ; Animals ; Apolipoproteins E ; biosynthesis ; genetics ; Gene Expression ; Hippocampus ; metabolism ; Learning ; drug effects ; Membrane Proteins ; biosynthesis ; genetics ; Memory ; drug effects ; Mice ; Presenilin-1 ; Presenilin-2 ; tau Proteins ; biosynthesis ; genetics

Alzheimer's disease (AD) is the most common cause of dementia in elderly population. There are two hallmark pathological lesions: the intracellular neurofibrillary tangles (NFTs) and the extracellular amyloid deposits in the senile plaques (SP). The NFTs are aggregates of hyperphosphorylated microtubule Tau protein. The amyloid deposits in the SP are the beta-amyloid (Abeta) peptides-Abeta40 and Abeta42. The Abeta peptides are derived from the amyloid precursor protein (APP) which is considered very important for the AD pathogenesis. In recent years, studies have focused on understanding the generation of Abeta peptides by the alpha-, beta- and gamma- secretase activity on APP, as cause and progression of both familial and sporadic AD (FAD and SAD). This review covers the trafficking and processing of APP, the amyloid cascade hypothesis in AD pathogenesis, the mutations in the genes encoding APP, PS1 and PS2 of early-onset and late-onset AD. The risk factor apolipoprotein E (ApoE) for AD and therapeutic anti-beta-amyloid vaccination strategies for prevention of AD are also discussed.
Alzheimer Disease ; genetics ; metabolism ; pathology ; therapy ; Alzheimer Vaccines ; immunology ; Amyloid beta-Peptides ; antagonists & inhibitors ; genetics ; immunology ; metabolism ; Amyloid beta-Protein Precursor ; genetics ; metabolism ; Animals ; Apolipoproteins E ; genetics ; Humans ; Immunotherapy, Active ; Membrane Proteins ; genetics ; Peptide Fragments ; genetics ; Plaque, Amyloid ; pathology ; Presenilin-1 ; Presenilin-2

OBJECTIVETo detect the estrogenic activity of genistein and apigenin with ER-positive cell line MCF-7 human breast cancer cells.

METHODMTT method was adopted to study the impact of genistein and apigenin on MCF-7 proliferation in vitro. Real-time RT-PCR method was used to detect their impact on ERalpha, ERbeta, PR and PS2 mRNA expression levels.

RESULTGenistein and apigenin promoted the proliferation of MCF-7. Genistein 1 x 10(-10) mol x L(-1) group showed a significant increase in the expression of ERa mRNA levels or a 17. 76 times more than the control group and a 1.75 times more than the E2 group. Apigenin notably promoted the PR mRNA expression or a 4. 57 times more than the control group and a 1.11 times more than the E2 group. Both of them had different effect in promoting ERalpha, ERbeta, PR or PS2 mRNA.

CONCLUSIONBoth genistein and apigenin have a strong estrogen-like effect. Although they have different effect in promoting estrogenic response genes (such as ERa, ERbeta, PR and PS2 mRNA), genistein shows a stronger activity than apigenin. It also suggests that the signaling pathways of phytoestrogens showing estrogen-like effect are not completely identical with estrogen pathways. The B-cycle position of flavonoids is one of the key sites to estrogen-like activity, and isoflavones (cycle B on site 3) show stronger estrogen-like activity than flavones (B-cycle lies in site 2).

Apigenin ; pharmacology ; Cell Proliferation ; drug effects ; Estrogen Receptor alpha ; genetics ; metabolism ; Estrogen Receptor beta ; genetics ; metabolism ; Female ; Gene Expression ; drug effects ; Genistein ; pharmacology ; Humans ; MCF-7 Cells ; Phytoestrogens ; pharmacology ; Presenilin-2 ; genetics ; metabolism

OBJECTIVEThis report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice.

METHODSThe protein level of Abeta(42) in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately.

RESULTSSignificant decrease of Abeta(42) was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months.

CONCLUSIONOxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Abeta(42). Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.

Age Factors ; Alzheimer Disease ; genetics ; metabolism ; physiopathology ; Amyloid beta-Peptides ; urine ; Animals ; Deoxyguanosine ; analogs & derivatives ; urine ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; methods ; Glutathione ; metabolism ; Hydrazines ; metabolism ; Lipid Peroxidation ; genetics ; Malondialdehyde ; metabolism ; Mice ; Mice, Inbred CBA ; Mice, Knockout ; physiology ; Oxidation-Reduction ; Oxidative Stress ; physiology ; Peptide Fragments ; urine ; Presenilin-1 ; deficiency ; Presenilin-2 ; deficiency ; Spectrophotometry, Atomic ; methods ; Superoxide Dismutase ; metabolism

OBJECTIVETo investigate the estrogenic activity of icariin and genistein with estrogen-dependent human breast cancer (MCF-7) cells.

METHODMCF-7 cells were incubated with media containing 5% charcoal dextran-treated FBS in phenol red-free media for 48 h. CCK-8 kit was used to study the impact of defferent concentration of icariin and genistein on MCF-7 proliferation in vitro. Optimal concentration icariin and genistein were added into medium and total RNA was isolated after 12, 24, 36, 48 h. The gene expression of ERalpha, ERbeta, PS2, and PR were investigated by Real-time RT-PCR Total protein was also isolated and secretion of ERalpha, ERbeta, PS2, and PR were examined by Western blot.

RESULT10 micromol x L(-1) icariin and genistein could promote the proliferation of MCF-7 evidently. However, the ability of genistein to promote the proliferation was better than icariin. With the concentration of 10 micromol x L(-1), genistein group had a stronger expression of ERa, PS2 and PR mRNA levels than icariin while ERbetaexpression had no significant difference in two group. The same effects were detected by western blotting.

CONCLUSIONBoth genistein and icariin have a strong estrogen-like effect, but the estrogenic activity of genistein is stronger than icariin. It showed that the activity of icariin is stron-ger than genistein to promote ROB maturation. So it must be that icariin promotes the maturation of osteoblasts in vitro by a estogen-independent mechanism.

Cell Proliferation ; drug effects ; Estrogen Receptor alpha ; genetics ; metabolism ; Estrogen Receptor beta ; genetics ; metabolism ; Estrogens ; pharmacology ; Flavonoids ; pharmacology ; Gene Expression Regulation ; drug effects ; Genistein ; pharmacology ; Humans ; MCF-7 Cells ; Osteoblasts ; cytology ; drug effects ; metabolism ; Presenilin-2 ; metabolism

OBJECTIVETo observe the effects of Huannao Yicong Formula (, HYF) on learning and memory and it's regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer's disease.

METHODSSixty APP/PS1 transgenic mice, randomly allocated into 4 groups, the model group, the donepezil group (0.65 mg/kg), HYF low-dose group (HYF-L, 5.46 g/kg) and HYF high-dose group (HYF-H, 10.92 g/kg), 15 for each group. Another 15 C57BL/6J mice with the same age and same genetic background were allocated into the control group, proper dosage of drugs or distilled water were given by intragastric administration once daily for 12 weeks. After 12 weeks of administration, the learning and memory abilities of mice in each group was evaluated by the morris water maze test, amyloid precursor protein (APP), Aβand Aβlevels in hippocampus were detected by enzyme-linked immunosorbent assay, γ-secretase was detected by dual luciferase assaying, the levels of APH-1a, hypoxia-inducible factor 1α (HIF-1α), cAMP response element-binding protein (CREB) and PEN-2 and their mRNA expression was measured by Western blot and real-time polymerase chain reaction.

RESULTSHYF can ameliorate learning and memory deficits in APP/PS1 transgenic mice by decreasing the escape latency, improving the number of platform crossing and swimming speed (P<0.01, P<0.05). HYF can decrease the levels of APP, Aβ, Aβand the activity of γ-secretase in hippocampus of Alzheimer's disease model mice. HYF can down-regulate the levels of CREB and PEN-2 and the expression of their mRNA.

CONCLUSIONHYF can improve the learning and memory ability by inhibiting the activity of γ-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer's disease.

Amyloid Precursor Protein Secretases ; metabolism ; Amyloid beta-Protein Precursor ; metabolism ; Animals ; Cyclic AMP Response Element-Binding Protein ; genetics ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Endopeptidases ; genetics ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Gene Expression Regulation ; drug effects ; Hippocampus ; drug effects ; metabolism ; pathology ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Immunohistochemistry ; Learning ; drug effects ; Male ; Memory Disorders ; drug therapy ; genetics ; Mice, Inbred C57BL ; Mice, Transgenic ; Presenilin-1 ; metabolism ; Presenilin-2 ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Signal Transduction ; drug effects