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DHEA on Aβ_ (25-35) mouse hippocampal neurogenesis and its molecular mechanism

Author: LiLiang
Tutor: ChenLing
School: Nanjing Medical University
Course: Physiology
Keywords: Alzheimer's disease β- amyloid DHEA Dehydroepiandrosterone sulfate Neurogenesis Phosphatidylinositol 3 - kinase Mammalian target of rapamycin
CLC: R749.16
Type: Master's thesis
Year: 2010
Downloads: 146
Quote: 0
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Abstract


Background adult mammalian hippocampus dentate gyrus neural stem cells can differentiate into nerve cells called neurogenesis. Neurogenesis including stem cell proliferation, survival and differentiation of precursor cells, newborn neurons mature synapse formation and neural circuits integrating four stages. These new neurons and mature granule cells have similar structural and functional properties, with the CA3 region of the pyramidal cells establish synaptic contacts and generate evoked synaptic transmission and synaptic plasticity. Hippocampal neurogenesis has also been associated with spatial cognitive function. Thus, adult neurogenesis is considered to replace and repair due to natural aging or diseases caused by neuronal loss, to maximize the maintenance of the structure and function of the brain. Alzheimer's disease (Alzheimer's disease, AD) is a kind of progressive cognitive dysfunction is characterized by degenerative diseases of the nervous system. Whether new neurons can replace neurons lesions improve cognitive dysfunction in AD AD research has become a new target. Study found, AD brain hippocampal stem cell proliferation is on the increase, precursor cells differentiate into neurons was significantly reduced, while the survival rate of newborn neurons was significantly reduced, and the growth of new neurons abnormal protrusion. These studies have confirmed, AD brain nerve regeneration process of serious damage, suggesting nerve aplasia may be cognitive function decline AD important pathological mechanisms. Steroid hormone DHEA (Dehydroepiandrosterone, DHEA) and its sulfate ester DHEAS is the most abundant central nervous system, the most active one nerve steroid hormones. Some data indicate that, DHEA / DHEAS levels in the increased incidence of AD and increased deposition of Aβ in the brain showed a positive correlation. DHEA can promote neurite growth and proliferation of neural stem cells. However, about DHEA / DHEAS in AD brain aplastic role has been reported so far yet to see. Recent studies reported, PI3K (phosphoinositide 3-kinase)-Akt (protein kinase B)-mTOR (Mammalian Target Of Rapamycin, a serine / threonine protein kinase) signaling pathway in the adult cells play a key role in regulating and propose PI3K-Akt-mTOR signaling pathway and the pathogenesis of Alzheimer's disease. Purpose 1. Determine Aβ ( 25-35 ) fragment (Aβ 25-35 ) intracerebroventricular injection on hippocampal nerve regeneration; 2. Detect whether DHEA can improve Aβ 25-35 -induced nerve aplasia; 3. clarify DHEA prevents Aβ 25-35 damage to the molecular mechanisms of neuronal regeneration. Methods Part I: 1. Using Aβ 25-35 intracerebroventricular injection preparation cognitive dysfunction Aβ 25-35 mouse model; 2 with BrdU (5 - bromo- deoxyuridine) labeled mitotic phase of the cell, and in the last 24 hours after BrdU injection, 7 days, 14 days, 21 days and 28 days by immunohistochemical method to detect hippocampal DG area BrdU-positive cells (BrdU Cell ), to determine the Aβ 25-35 of cell proliferation (24 hours age-BrdU cells) and survival (7 days of age - 14 days of age - and 28 days of age-BrdU cells) of; 3 . stained with Hoechst granular zone concept Chahaimaya newborn neuronal apoptosis; 4. Doublecortin (DCX) immunostaining was observed newborn neurons neurite outgrowth; 5 intraperitoneal administration of different concentrations of DHEA, DHEA on Aβ determine 25-35 mouse nerve aplasia role, and the role of DHEA dose-dependent; 6. use DHEA precursors PREG (Pregnenolone, pregnenolone), DHEA metabolites TE (Testosterone, Testosterone), E2 (Estradiol, estradiol) intraperitoneal administration, observation DHEA to improve the role of AD brain aplastic specificity. Part II: 1. Observe the sigma-1 (σ1) receptor antagonist NE100, NMDA receptor antagonist MK801, IP3 receptor antagonist 2-APB on DHEA protection Aβ 25-35 disorders affecting nerve regeneration in mice to determine the protective effect of DHEA target receptor; 2. observe σ1 receptor agonist PRE084 whether the proposed protective effect of DHEA; 3 with a PI3K inhibitor LY294002, mTOR inhibitor Rapamycin (sirolimus ADM), ERK kinase (MEK) inhibitor U0126 and PKC inhibitor Chelerythrine Chloride (chelerythrine base) pretreatment, determine DHEA protection Aβ 25-35 mouse nerve regeneration intracellular signal transduction pathway; 4 Take the hippocampus specimens Akt, mTOR, ERK1 / 2 and p70s6k the western blot analysis to determine the molecular mechanisms of the protective effect DHEA. Results Part I: 1. Compared with the control group of mice, Aβ 25-35 mouse dentate gyrus 24 hours age-BrdU cells increased about three times the 28-day-old-BrdU cells showed 50% reduction; 2 mice compared with the control group, Aβ 25-35 mouse dentate gyrus of newborn neurons projecting the number and length were significantly reduced; 3 with the control group of mice comparison, Aβ 25-35 mouse dentate gyrus region of sub-particles significantly increased the number of apoptotic cells; 4. DHEA treatment can improve concentration-dependent Aβ 25-35 28 days-BrdU mouse cells were significantly reduced, to protect the growth of neurites, and does not affect the differentiation of new neurons. Part II: 1.σ1 DHEA receptor antagonist NE100 protection can prevent Aβ 25-35 newborn hippocampal neuronal survival; 2.σ1 can simulate DHEA receptor agonist PRE084 role in protecting Aβ 25-35 newborn mouse hippocampus neuronal survival; 3. PI3K inhibitor LY294002 and the mTOR inhibitor Rapamycin prevents DHEA protection Aβ 25-35 Mice newborn hippocampal neuronal survival; 4. mTOR inhibitor Rapamycin can damage non-Aβ mice (normal mice) newborn neurons neurite growth; 5 mice compared with the control group, Aβ 25-35 mouse hippocampal Akt, mTOR, and p70s6k phosphorylation activity decreased significantly; 6. DHEA can improve Aβ 25-35 mouse hippocampal Akt, mTOR, and p70s6k phosphorylation activity. Conclusion 1. Aβ 25-35 damage of neonatal neurite growth and survival of new neurons; 2. DHEA can prevent Aβ 25-35 damage newborn neurons neurite outgrowth and the survival of newborn neurons; 3. DHEA protection Aβ 25-35 mouse hippocampal neurogenesis target molecule is σ1 receptor; 4. Aβ 25-35 down PI3K -Akt-mTOR-p70s6k signaling molecules that cause neonatal neurite growth retardation; 5. DHEA can prevent Aβ 25-35 down PI3K-Akt-mTOR-p70s6k signaling molecule pathways.

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