Shuli Sheng

GEPT Extract Reduces Aβ Deposition by Regulating the Balance Between Production and Degradation of Aβ in APPV717I Transgenic Mice

BACKGROUND Accumulation of beta-amyloid peptide (Abeta) in the brain is a primary influence driving Alzheimers disease (AD) pathogenesis. The disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between production and clearance of Abeta. A major therapeutic strategy for AD should be to decrease deposition of Abeta by the inhibition of its production and the facilitation of its degradation. Hence, the primary aim of this study was to investigate effects of GEPT, a combination of herbal extracts, on Abeta levels, beta- and gamma-secretases substrate (BACE1 and PS1, respectively) associated with production of Abeta, and insulin-degrading enzyme (IDE) and neprilysin (NEP) related to degradation of Abeta in the brain. METHODS Three-month-old-male APPV717I mice were randomly divided into five groups (n=6 per group): (i) APP mice alone were given distilled water, (ii) APP donepezil mice were treated with donepezil (0.92 mg/kg/d), and (iii-v) APP mice treated with GEPT low dose (0.75 g/kg/d), middle dose (1.5 g/kg/d), and large dose (3.0 g/kg/d) for 8 months. Three-month-old-male C57BL/6J mice (n=6) for vehicle were given distilled water for 8 months. Immunohistochemistry and Western blot analysis were used in determining amyloid precursor protein (APP), Abeta1-42, BACE1, PS1, IDE and NEP in hippocampal CA1 region and hippocampal tissue homogenates. RESULTS Expression level of Abeta1-42 in the large GEPT dose was significantly lower than those in APP alone or APP treated with donepezil, and decreased to the level of vehicle mice. Similarly, a ratio calculated from the densitometric measures of Abeta1-42 protein/beta-actin in the large dose also was significantly lower than those in APP mice alone or APP mice treated with donepezil, and even reduced to the level of vehicle mice. Expression of PS1 in the large GEPT dose was significantly lower than that of APP mice alone and decreased to those in vehicle mice as well. A decreased level of BACE1 appeared, respectively, in APP mice treated with the large GEPT dose or donepezil but was still much greater than the level of vehicle mice. In contrast, NEP and IDE showed a significantly higher expression in APP mice treated with either the large dose or the middle dose of GEPT compared to APP mice alone or donepezil, and were even increased in level compared to vehicle mice. CONCLUSION The combination of GEPT extracts can reduce levels of endogenous Abeta peptide in APPV717I transgenic mice through the inhibition of PS1 activity rather than BACE1 and the promotion of IDE and NEP activity. Lower-expression of PS1 and over-expression of IDE or NEP may be helpful in potentially lowering brain Abeta levels in subjects with AD, and hence GEPT appears to offer potential that should be explored in AD.

Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons

Type 2 diabetes recently has been identified as a risk factor for developing Alzheimers disease (AD). The main reason for this appears to be insulin signaling failure in the brain. Furthermore, cholinergic neurons are particularly affected in the brains of AD patients. The aim of the present study is to investigate if insulin signaling-related proteins are co-located with cholinergic neuron in the CA1 region of hippocampus of mice, which could explain the early loss of cholinergic neurons in AD. Using immunohistochemistry, the insulin signaling-related proteins, such as insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), protein kinase B (PKB, also named Akt), glycogen synthase kinase-3beta (GSK-3beta) and insulin-degrading enzyme (IDE) were analysed. Choline acetyltransferase (ChAT) was selected as a marker of cholinergic neurons. In the CA1 region of hippocampus of mice, several of the insulin signaling-related proteins we had chosen are co-located with ChAT, and most double immunoreactive positive cells were pyramidal cells. The coexistences indicated that the insulin signaling may play an important part in the activities of cholinergic neurons, and the impairment of the pathway may be important in the mechanisms that underlie neurodegeneration in AD.

A novel neurotrophic peptide: APP63-73.

The objective of this study was to find out which N-terminal segment/s of amyloid precursor protein (APP) has any neurotrophic properties, since soluble APP-&agr; (sAPP-&agr;) has neurotrophic effects. We investigated neurotrophic properties of eight peptide segments of N-terminal APP. The APP63-73 was able to enhance neuronal growth; augment axonal and cell body growth in human neuroblastoma cell line, SH-SY5Y. Neurotrophic effects of chronic APP63-73 treatment were assessed in vivo using streptozotocin-induced diabetes and ovariectomized rats. Thus, this study demonstrated that APP63-73 peptide has neurotrophic effects both in vivo and in vitro.

Rosiglitazone Improves Learning and Memory Ability in Rats With Type 2 Diabetes Through the Insulin Signaling Pathway

Abstract:Diabetes mellitus (DM) is associated with moderate cognitive deficits and neurophysiologic and structural changes in the brain, a condition that is referred to as diabetic encephalopathy. This study was performed to investigate the effect of rosiglitazone (RSG) on learning and memory in rats with DM and elucidate possible mechanisms underlying this condition. Thirty-two male Sprague-Dawley rats were randomly divided into 4 groups: control (C, n = 8), DM (n = 8), RSG-administered control (C + RSG, n = 8) and RSG-administered DM groups (DM + RSG, n = 8). At 8 weeks after drug administration, Morris water maze was used to perform a training and probe trial to detect spatial learning and memory abilities. Western blot and immunohistochemistry were also used to detect changes in proteins involved in the insulin signal transduction pathway, such as the insulin receptor, insulin receptor substrate-1, protein kinase B, phosphorylated cAMP response element–binding protein and B-cell lymphoma 2, in the hippocampus of the rats. This study found that RSG could normalize the impaired insulin signal transduction in type 2 DM. The authors showed that RSG modulated the central insulin signaling axis.

Development of a Novel Urine Alzheimer-Associated Neuronal Thread Protein ELISA Kit and Its Potential Use in the Diagnosis of Alzheimer's Disease

Alzheimers disease (AD) is an age‐related chronic degenerative disease that damages the nervous system. A noninvasive and simple method for early detection of AD is extremely important for the diagnosis and prognosis of AD. Thus, we aimed to develop an enzyme‐linked immunosorbent assay (ELISA) kit to detect urine Alzheimer‐associated neuronal thread protein (AD7C‐NTP), and to evaluate its clinical value for the diagnosis of AD.

Neurotrophic effects of amyloid precursor protein peptide 165 in vitro.

Diabetic encephalopathy is one of the risk factors for Alzheimers disease. Our previous findings indicated that animals with diabetic encephalopathy exhibit learning and memory impairment in addition to hippocampal neurodegeneration, both of which are ameliorated with amyloid precursor protein (APP) 17-mer (APP17) peptide treatment. Although APP17 is neuroprotective, it is susceptible to enzymatic degradation. Derived from the active sequence structure of APP17, we have previously structurally transformed and modified several APP5-mer peptides (APP328-332 [RERMS], APP 5). We have developed seven different derivatives of APP5, including several analogs. Results from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on human neuroblastoma SH-SY5Y cells in the present study showed that P165 was the most neuroprotective APP5 derivative. Furthermore, we tested the effects of APP5 and P165 on the number of cells and the release of lactate dehydrogenase. Western immunoblot analyses were also performed. The digestion rates of P165 and APP5 were determined by the pepsin digestion test. P165 resisted pepsin digestion significantly more than APP5. Therefore, P165 may be optimal for oral administration. Overall, these findings suggest that P165 may be a potential drug for the treatment of diabetic encephalopathy.

Detecting urinary AD7C-NTP level to diagnose Alzheimer's disease

Age (years) 69.165.4 72.866.3 74.166.9 Sex (male/female) 38/62 88/203 54/150 Education (years) 9.565.1 8.265.1 8.065.1 Body mass index (kg/m) 4.262.4 24.163.4 23.163.6 Total cholesterol (mmol/L) 82.9632.2 83.7637.3 80.4637.5 LDL-cholesterol (mmol/L) 58.2646.4 64.9648.4 71.0651.6 Triglyceride (mmol/L) 111.8680.6 101.6674.4 108.4676.8 Current smoking (+/-) 6/94 17/274 9/195 Habitual alcohol intake (+/-) 36/64 76/215 44/160 Presence of cardiovascular disease (+/-) 4/96 37/254 9/195 Presence of hypertension (+/-) 52/48 147/144 92/112 Presence of diabetes mellitus (+/-) 18/82 65/226 38/165 Systolic blood pressure (mmHg) 133.0620.1 138.2618.9 135.1619.2 Ankle brachia index 1.2760.2 1.1660.2 1.1760.18

The changes of learning and memory abilities and insulin signal pathway on hippocampal neurons of diabetic mice

Structural vascular abnormality was observed in cortical branch of cerebral arteries in KK-A mice. Leakage of EB dye was markedly increased in KKA mice compared with C57BL/6J mice. Administration of telmisartan significantly decreased the EB extravasations. Co-treatment with GW9662 attenuated telmisartan-mediated protective effects of BBB in KK-A mice. Conclusions: These findings suggest that telmisartan has protective effects on cognitive decline in diabetic mice, partly due to prevention of BBB disruption via possible synergistic activation of PPAR-g as well as blockade of angiotensin II type 1 receptor signaling.

P2-369: GETO reduces Aβ deposition by increasing the activity of neprilysin

Jinzhou Tian, Jing Shi , Yi Xu, Junxiang Yin , Shuli Sheng, Pengwen Wang, Rong Wang, Leiming Zhang , Chongshun Song , Yongyan Wang, BUCM Neurology Centre, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Department of Preclinical Medicine, Hubei College of Chinese Medicine, Wuhan, China; Institute of Geriatrics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Lab. of Neurobiochemistry, Xuanwu Hospital, CUMS, Beijing, China; China Academy of Chinese Medical Sciences, Beijing, China. Contact e-mail: johnsontian@hotmail.com

P-013: Effect of geto combination on production and degradation of aβ in the brain of APPV717i transgenic mice

Jinzhou Tian, Jing Shi, Yi XU, Junxiang Yin, Shuli Sheng, Yongyan Wang, Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing, China; Hubei University of Traditional Chinese Medicine School of Basic Medicine, Wuhan, China; Beijing University of Chinese Medicine, Dongzhimen Hospital, Beijing, China; Beijing University of Chinese Medicine Institute of Geriatrics, Beijing, China; Capital University of Medical Sciences Xuanwu Hospital, Beijing, China; China Academy of Chinese Medicine, Beijing, China. Contact e-mail: shijing87@hotmail.com