Zhijuan Ji

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.

P2-447: Effect of APP5-mer peptide and its analog P165 on proliferation and differationation of neural stem cells in rat brain

teen healthy young male subjects participated in a randomised, double-blind, placebo-controlled, cross-over study. Subjects were scanned twice, once following placebo and once following GSK189254 (1 mg) administered orally. Subjects performed a paired associate learning task (PAL) and a visual delayed matching to sample task (DMTS) during scanning. The PAL involved repeated presentation of a set of patterns, allowing separate investigation of encoding, retrieval and learning. Imaging data were analysed with SPM5 and performance data with SPSS. Results: In the PAL task, encoding and retrieval elicited activation of networks incorporating lateral and medial frontal regions, and the posterior parietal lobes. GSK189254 did not modulate the signal in these networks. However, the amplitude of activation in a region between the mamillary bodies and posterior hypothalamus (consistent with the location of histaminergic neurons), showed a quasi-linear relationship with the order of repetition of each set of patterns, suggesting a regional effect of learning. GSK189254 significantly modified the slope of this relationship. Faster reaction times on GSK189254 correlated significantly with the amplitude of signal change in this region. In the DMTS task, GSK189254 was associated with increased activation at the parieto-occipital junction, especially for responses after a short delay (3 s) condition. The increase in activity due to GSK189254 was correlated with shorter response latency. Conclusions: GSK189254 may modulate learning via stimulation of histaminergic neurons. It may also enhance processing during delayed recall in episodic memory task via modulation of activity in the parieto-occipital junction which is involved in visuospatial attention. Both cognitive tasks are impaired in AD. These findings suggest possible mechanisms by which GSK189254 could enhance cognition in impaired populations.

The relationship between hypotensive effect and structure of adrenomedullin

Adrenomedullin (AM) is a novel hypotensive peptide isolated from human pheochromocytoma in 1993. It consists of 52 amino acid residues with a disulfide bond from position 16 to 21. In order to determine the relationship between hypotensive effect and structure of AM, we synthesized seven fragments of human AM (hAMI15, 16-52,23-52,22-42,26-42,28-42,. 40-52) and one fragment of rat AM (rAMl-13) by solid-phase method. These fragments purified by HPLC were injected intravenously to rats and the blood pressure(Bp) was monitored.